Compositions and methods for acylating lactams

ABSTRACT

This disclosure provides methods for intermolecular enantioselective C-acylation of lactams with quaternary stereogenic centers by applying a chiral Ni catalyst. The methods comprise treating a lactam with a chiral Ni catalyst, an aryl nitrile, and an aryl halide.

RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application62/306,851, filed Mar. 11, 2016, the content of which is incorporatedherein by reference.

GOVERNMENT SUPPORT

This disclosure was made with government support under Grant NumberGM080269, awarded by the National Institutes of Health. The governmenthas certain rights in the disclosure.

BACKGROUND

The catalytic enantioselective construction of quaternary stereocentersremains a challenging problem in synthetic chemistry. Catalyticenantioselective construction of quaternary stereocenters remains achallenging problem in synthetic chemistry.^(1a,2) Catalyticenantioselective reactions of enolates with electrophiles are among themost useful processes to construct quaternary stereocenters.³ In thisarea, remarkable success has been achieved in the context of reactionssuch as enantioselective alkylations, conjugate additions, arylations,and aldol reactions.^(1b,c,d)

By contrast, there remains a paucity of enantioselective C-acylationreactions of enolates that enable access to β-keto carbonyl compounds.Recently, intramolecular acyl transfer strategies such as asymmetricStegich and Black rearrangements have been developed.^(4,5) However,limited examples are reported for intermolecular enantioselectiveC-acylation of enolates or enol ethers.^(6,7,8) A challenging issue forC-acylation is competitive O-acylation, leading to mixtures of C- andO-acylated products.⁹ Fu has reported an excellent strategy forC-acylation of silyl ketene acetals utilizing planar-chiral4-(pyrrolidino)pyridine (PPY) catalysts, which allows access to cyclicand acyclic β-keto esters with excellent enantioselectivity.⁶Alternative strategies involve isothiourea or thiourea catalyzedC-acylation of silyl ketene acetals as reported by Smith andJacobsen.^(7,8) Consequently, there remains a significant need todevelop new reaction protocols that enable access to β-keto carbonylcompounds.

SUMMARY

This disclosure provides methods for intermolecular enantioselectiveC-acylation of lactams comprising treating a lactam with a chiral Nicatalyst, an aryl nitrile, and an aryl halide.

The present disclosure provides methods for preparing a compound offormula (I):

comprising treating a compound of formula (II):

or a salt thereof;

-   with a Ni(0) catalyst comprising a chiral ligand;-   an aryl nitrile; and-   an aryl halide;-   wherein, as valence and stability permit,-   R¹ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or    —NR¹⁰R¹¹;-   or R¹ or a substituent on ring A taken together with a substituent    on ring A and the intervening atoms, form an optionally substituted    aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or    heterocycloalkenyl group;-   R² represents substituted or unsubstituted alkyl, alkenyl, alkynyl,    aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl,    heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkoxy, amino, or halo;-   R¹⁰ and R¹¹ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl; and-   ring A represents an optionally substituted heterocycloalkyl or    heterocycloalkenyl group.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows structure of exemplary enantioenriched phosphine ligands.

FIG. 2 shows a possible reaction mechanism of enantioselectiveC-acylation.

DETAILED DESCRIPTION I. Definitions

The definitions for the terms described below are applicable to the useof the term by itself or in combination with another term.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbyl-C(O)—, preferably alkyl-C(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl-C(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond that is straight chained or branchedand has from 1 to about 20 carbon atoms, preferably from 1 to about 10unless otherwise defined. The term “alkenyl” is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acylsuch as an alkylC(O)), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude substituted and unsubstituted forms of amino, azido, imino,amido, phosphoryl (including phosphonate and phosphinate), sulfonyl(including sulfate, sulfonamido, sulfamoyl and sulfonate), and silylgroups, as well as ethers, alkylthiols, carbonyls (including ketones,aldehydes, carboxylates, and esters), —CF₃, —CN and the like. Exemplarysubstituted alkyls are described below. Cycloalkyls can be furthersubstituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls,carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-tirfluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkyl-S—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R¹⁰ independently represent a hydrogen or hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R¹⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group. An aralkyl group is connected to the rest of themolecule through the alkyl component of the aralkyl group.

The term “aralkenyl”, as used herein, refers to an alkenyl groupsubstituted with an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 10-membered ring, more preferably a 6- to10-membered ring or a 6-membered ring. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline,and the like. Exemplary substitution on an aryl group can include, forexample, a halogen, a haloalkyl such as trifluoromethyl, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acylsuch as an alkylC(O)), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R⁹ and R¹⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo [4. 2.0] octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “cycloalkylalkyl”, as used herein, refers to an alkyl groupsubstituted with a cycloalkyl group.

The term “carbonate” is art-recognized and refers to a group —OCO₂-R¹⁰,wherein R¹⁰ represents a hydrocarbyl group.

The term “carboxyl”, as used herein, refers to a group represented bythe formula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR¹⁰ whereinR¹⁰ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group.

The terms “hetaralkenyl” and “heteroaralkenyl”, as used herein, refersto an alkenyl group substituted with a heteroaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include 5- to 10-membered cyclic or polycyclic ring systems,including, for example, pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, andthe like. Exemplary optional substituents on heteroaryl groups includethose substituents put forth as exemplary substituents on aryl groups,above.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocycloalkyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocycloalkyl” and “heterocyclic” also include polycyclic ringsystems having two or more cyclic rings in which two or more carbons arecommon to two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/orheterocycloalkyls. Heterocycloalkyl groups include, for example,piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, andthe like.

The term “heterocycloalkylalkyl”, as used herein, refers to an alkylgroup substituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The term “carbamate” is art-recognized and refers to a group —CN.

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto. A “silyl ether” refers to a silyl grouplinked through an oxygen to a hydrocarbyl group.

Exemplary silyl ethers include —OSi(CH₃)₃ (—OTMS), —OSi(CH₃)_(2t)-Bu(—OTBS), —OSi(Ph)_(2t)-Bu (—OTBDPS), and —OSi(iPr)₃ (—OTIPS).

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a haloalkyl, a hydroxyl, a carbonyl (such as acarboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (suchas a thioester, a thioacetate, or a thioformate), an alkoxyl, aphosphoryl, a phosphate, a phosphonate, a phosphinate, an alkyl, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat substituents can themselves be substituted, if appropriate. Unlessspecifically stated as “unsubstituted,” references to chemical moietiesherein are understood to include substituted variants. For example,reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R⁹ and R¹⁰ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R¹⁰, wherein R¹⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof. In some embodiments, asulfonate can mean an alkylated sulfonate of the formula SO₃(alkyl).

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR¹⁰ or—SC(O)R¹⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogenprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (esterified) or alkylated such as benzyl and tritylethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers (e.g., TMS or TIPS groups), glycol ethers, such as ethyleneglycol and propylene glycol derivatives and allyl ethers.

II. Description.

This disclosure is based on the discovery of a novel C-acylationreaction that generates an α-quaternary substituted lactam. The methodscomprise treating a lactam with a chiral Ni catalyst, an aryl nitrile,and an aryl halide. For example, the Ni-catalyzed three-componentcoupling of lactam enolates, benzonitriles, and aryl halides produceβ-keto lactams after treatment with acid. Use of a ligand, preferably achiral ligand, and the addition of LiBr enables the construction ofquaternary stereocenters on α-substituted lactams to form β-ketolactams.

According to embodiments of the present disclosure, a wide range ofstructurally-diverse, functionalized products are prepared by astereoselective method of nickel-catalyzed enantioselective enolateacylation. This chemistry is useful in the synthesis of lactams, such asβ-lactam antibiotics, and for the construction of novel building blocksfor medicinal and polymer chemistry.

III. Methods of the Disclosure

In certain aspects, the present disclosure provides for the preparationof a compound of formula (I):

comprising treating a compound of formula (II):

or a salt thereof;

-   with a Ni(0) catalyst comprising a chiral ligand;-   an aryl nitrile; and-   an aryl halide;-   wherein, as valence and stability permit,-   R¹ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or    —NR¹⁰R¹¹;-   or R¹ or a substituent on ring A taken together with a substituent    on ring A and the intervening atoms, form an optionally substituted    aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or    heterocycloalkenyl group;-   R² represents substituted or unsubstituted alkyl, alkenyl, alkynyl,    aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl,    heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkoxy, amino, or halo;-   R¹⁰ and R¹¹ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl; and-   ring A represents an optionally substituted heterocycloalkyl or    heterocycloalkenyl group.

In certain embodiments, the compound of formula (I) is represented byformula (Ia):

and the compound of formula (II) is represented by formula (IIa):

wherein:

-   R⁴ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or    —NR¹⁰R¹¹;-   R⁵ and R⁶ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl, ether, thioether,    ester, amido, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;-   B, D, and E independently for each occurrence represent, as valence    permits, O, S, NR⁴, CR⁵R⁶, C(O), CR⁵, or N; provided that no two    adjacent occurrences of N, B, D, and E are NR⁴, O, S, or N;-   or any two occurrences of R¹, R⁴, R⁵, and R⁶ on adjacent N, B, D, or    E groups, taken together with the intervening atoms, form an    optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl,    heterocycloalkyl, or heterocycloalkenyl group;-   each occurrence of    independently represents a double bond or a single bond as permitted    by valence; and-   m and n are integers each independently selected from 0, 1, and 2.

In certain embodiments, the sum of m and n is 0, 1, 2, or 3; that is,ring A is a 4-7 membered ring.

In certain embodiments, ring A is a heterocyclic ring.

In certain such embodiments, each occurrence of B, D, and E isindependently —CR⁵R⁶—, or —CR⁵—, or —C(O)—. In certain embodiments, E is—CR⁵—; and the sum of m and n is 0; that is, ring A is a 4 memberedring. In certain embodiments, R⁵ is selected from hydrogen, hydroxyl,halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl,alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, andacylamino.

In certain embodiments, ring A contains one or more double bonds, e.g.,one or more carbon-carbon double bonds.

In certain embodiments, the compound of formula (I) is represented byformula (Ib):

and the compound of formula (II) is represented by formula (IIb):

In some embodiments of the compounds disclosed herein,

-   R¹ is selected from optionally substituted alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, alkenyl, —C(O)alkyl, —C(O)aryl,    —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl),    —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), and —S(O)₂(aryl);-   R⁵ is selected from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,    alkoxy, aryloxy, alkylamino, amido, and acylamino; or-   R¹ and the occurrence of R⁵ on E are taken together to form an    optionally substituted heteroaryl, heterocycloalkyl, or    heterocycloalkenyl group.

In some embodiments,

-   R¹ is selected from optionally substituted alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, alkenyl, —C(O)alkyl, —C(O)aryl,    —C(O)aralkyl, —C(O)heteroaryl, —C (O)heteroaralkyl, —C(O)O(alkyl),    —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),    —C(O)O(heteroaralkyl), and —S(O)2(aryl); and-   R⁵ is selected from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,    alkoxy, aryloxy, alkylamino, amido, and acylamino.

In some embodiments, R¹ is selected from optionally substituted alkyl,aryl, aralkyl, alkenyl, —C(O)alkyl, —C(O)O(alkyl), —C(O)O(aryl),—C(O)O(aralkyl), and —S(O)₂(aryl). In some embodiments, R¹ issubstituted aryl.

In some embodiments, R¹ is a protecting group. In some embodiments, R¹is optionally substituted aralkyl, alkenyl, —C(O)alkyl, —C(O)O(alkyl),and —C(O)O(aralkyl). In some embodiments, R¹ is selected from acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trityl (e.g., triphenylamine) and substituted trityl groups,allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”), and benzylidenenamine.

In certain embodiments, R¹ and the occurrence of R⁵ on E are takentogether to form an optionally substituted heteroaryl, heterocycloalkyl,or heterocycloalkenyl group. In certain embodiments, R¹ and theoccurrence of R⁵ on E are taken together to form an optionallysubstituted heterocycloalkyl or heterocycloalkenyl group. For example, a4-membered lactam can be fused to an optionally substitutedheterocycloalkyl or heterocycloalkenyl group. For example, a penicillin,a cephalosporin, or a penem can be formed.

In certain embodiments, R² represents substituted or unsubstitutedalkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl,heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, or halo. In certainembodiments, R² is selected from alkyl, alkenyl, aryl, aralkyl,aralkenyl, or heteroaralkenyl, optionally substituted with halo, alkyl,haloalkyl, hydroxy, alkoxy, aryloxy, arylalkoxy, cyano, nitro, azido,—CO₂H, —C(O)O(alkyl), amino, alkylamino, arylamino, aralkylamino, oramido. In certain embodiments, R² is selected from alkyl, alkenyl, aryl,aralkyl, aralkenyl, or heteroaralkenyl, optionally substituted withhalo, alkyl, haloalkyl, alkoxy, aryloxy, or arylalkoxy.

In certain embodiments, the aryl nitrile is an optionally substitutedbenzonitrile or a napthonitrile. In certain embodiments, thebenzonitrile or the napthonitrile is optionally substituted with halo,alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, arylalkoxy, cyano, nitro,azido, —CO₂H, —C(O)O(alkyl), amino, alkylamino, arylamino, aralkylamino,or amido. In certain embodiments, the benzonitrile or the napthonitrileis optionally substituted with halo, alkyl, haloalkyl, or alkoxy.

In certain embodiments, the aryl halide is a phenyl halide. In certainembodiments, the aryl halide is selected from bromobenzene,chlorobenzene, iodobenzene, phenyl triflate, and chlorotoluene.

In certain embodiments, the method for preparing a compound of formula(I) comprises treating a compound of formula (II) with a Ni(0) catalystcomprising a chiral ligand; an aryl nitrile; and an aryl halide underacylation conditions.

In certain embodiments, the acylation conditions under which thecompound of formula (II) reacts to form a compound of formula (I)further comprise a base, such as hexamethyl-disilazane sodium salt(NaHMDS), KHMDS, LiHMDS, and lithium tert-butoxide (tBuOLi). In certainembodiments, the base is LiHMDS.

In certain embodiments, the acylation conditions under which thecompound of formula (II) reacts to form a compound of formula (I)further comprise a lithium salt, such as LiBr.

In certain embodiments, the acylation conditions under which thecompound of formula (II) reacts to form a compound of formula (I)further comprise adding an acidic solution.

In certain embodiments, the method yields a compound of formula (I) thatis enantioenriched.

Transition Metal Catalysts

Preferred transition metal catalysts of the disclosure are complexes ofnickel (0) comprising a chiral ligand.

It should be appreciated that typical transition metal catalysts havinga low oxidation state (e.g., (0) or (I)) suffer from air- andmoisture-sensitivity, such that these complexes of transition metalsnecessitate appropriate handling precautions. This may include thefollowing precautions without limitation: minimizing exposure of thereactants to air and water prior to reaction; maintaining an inertatmosphere within the reaction vessel; properly purifying all reagents;and removing water from reaction vessels prior to use. In certainembodiments, the Ni(0) catalyst is a precatalyst.

Exemplary Ni(0) catalysts that may be used in the methods of thedisclosure include Ni[(1,5-cyclooctadiene)₂], which is also referred toherein as Ni(COD)₂.

In certain embodiments, the transition metal catalysts of the disclosureare complexes of Ni(0) or Ni(II), such as Ni(COD)₂, NiCl₂, and NiBr₂.

In certain embodiments, the transition metal catalysts of the disclosureare complexes of Pd(0) or Pd(II). In certain embodiments, palladium (II)catalysts are typically robust, and are less sensitive to air andmoisture than their lower-oxidation state counterparts.

Exemplary Pd (II) catalysts that may be used in the methods of theinvention include Pd(OC(O)RC)₂, wherein R^(c) is optionally substitutedalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or(heterocycloalkyl)alkyl. Further exemplary Pd (II) catalysts includePd(OC(O)R^(c))₂, Pd(OC(═O)CH₃)₂ (i.e., Pd(OAc)₂), Pd(TFA)₂, Pd(acac)₂,PdCl₂, PdBr₂, PdCl₂(R²³CN)₂ (e.g., Pd(PhCN)₂Cl₂ and Pd(CH₃CN)₂Cl₂),PdCl₂(PR²⁴R²⁵R²⁶)₂, [Pd(η³-allyl)Cl]₂, and pre-formed Pd(II)-ligandcomplex, wherein R²³, R²⁴, R²⁵, and R²⁶ are independently selected fromhydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl,and substituted heteroatom-containing hydrocarbyl. In preferredembodiments, the transition metal catalyst is Pd(OAc)₂. Alternatively,the transition metal catalyst is Pd(OC(O)R^(c))₂, wherein R^(c) isdefined above. For example, R^(c) may be alkyl, substituted by one ormore halo or cyano groups.

To improve the effectiveness of the catalysts discussed herein,additional reagents may be employed, including, without limitation,salts, solvents, and other small molecules, such as a chiral ligand (seebelow). Preferred additives include a lithium salt, such as LiBr. Theseadditives are preferably used in an amount that is in the range of about0.1 equivalents to about 15 equivalents relative to the amount of thereactant, more preferably in the range of about 0.5 equivalents to about10 equivalents relative to the reactant, and most preferably in therange of about 2 equivalents to about 7 equivalents relative to thereactant.

In certain embodiments, additives include AgBF₄, AgOSO₂CF₃, AgOC(═O)CH₃,and bipyridine. These additives are preferably used in an amount that isin the range of about 1 equivalent to about 5 equivalents relative tothe amount of the catalyst.

A low oxidation state of a transition metal, i.e., an oxidation statesufficiently low to undergo oxidative addition, can be obtained in situ,by the reduction of transition metal complexes that have a highoxidation state. Reduction of the transition metal complex canoptionally be achieved by adding nucleophilic reagents including,without limitation, tetrabutylammonium hydroxide, tetrabutylammoniumdifluorotriphenylsilicate (TBAT), tetrabutylammonium fluoride (TBAF),4-dimethylaminopyridine (DMAP), tetramethylammonium hydroxide (e. g., asthe pentahydrate), KOH/1,4,7,10,13,16-hexaoxacyclooctadecane, sodiumethoxide, TBAT/trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, andcombinations thereof. When a nucleophilic reagent is needed for thereduction of the metal complex, the nucleophilic reagent is used in anamount in the range of about 1 mol % to about 20 mol % relative to thereactant, more preferably in the range of about 1 mol % to about 10 mol% relative to the substrate, and most preferably in the range of about 5mol % to about 8 mol % relative to the substrate.

For example, a Pd(II) complex can be reduced in situ to form a Pd(0)catalyst. Exemplary transition metal complexes that may be reduced insitu, include, without limitation, allylchloro[1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]palladium(II),([2S,3S]-bis [diphenylphosphino]butane)(η³-ally l)palladium(II)perchlorate,[S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η³-allyl)palladium(II)hexafluorophosphate (i.e., [Pd(S-tBu-PHOX)(allyl)]PF6), andcyclopentadienyl(η³-allyl) palladium(II).

The effectiveness of the catalysts discussed herein can be improved byadding nucleophilic reagents including, without limitation, NaHMDS,KHMDS, LiHMDS, tBuOLi, tetrabutylammonium hydroxide, tetrabutylammoniumdifluorotriphenylsilicate (TBAT), tetrabutylammonium fluoride (TBAF),4-dimethylaminopyridine (DMAP), tetramethylammonium hydroxide (e.g., asthe pentahydrate), KOH/1,4,7,10,13,16-hexaoxacyclooctadecane, sodiumethoxide, TBAT/trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, andcombinations thereof. When a nucleophilic reagent is added, thenucleophilic reagent is used in an amount in the range of about range ofabout 0.1 equivalents to about 10 equivalents relative to the amount ofthe reactant, more preferably in the range of about 0.1 equivalents toabout 5 equivalents relative to the reactant, and most preferably in therange of about 0.5 equivalents to about 2 equivalents relative to thereactant.

Accordingly, when describing the amount of transition metal catalystused in the methods of the disclosure, the following terminologyapplies. The amount of transition metal catalyst present in a reactionis alternatively referred to herein as “catalyst loading”. Catalystloading may be expressed as a percentage that is calculated by dividingthe moles of catalyst complex by the moles of the substrate present in agiven reaction. Catalyst loading is alternatively expressed as apercentage that is calculated by dividing the moles of total transitionmetal (for example, nickel) by the moles of the substrate present in agiven reaction.

In certain embodiments, the transition metal catalyst is present underthe conditions of the reaction from an amount of about 0.1 mol % toabout 20 mol % total nickel relative to the substrate, which is thecompound of formula (II). In certain embodiments, the catalyst loadingis from about 1 mol % to about 15 mol % total nickel relative to thesubstrate. In certain embodiments, the catalyst loading is from about 1mol % to about 14 mol %, about 1 mol % to about 12%, about 1 mol % toabout 10%, about 2 mol % to about 9 mol %, about 2.5 mol % to about 8mol %, about 3 mol % to about 7 mol %, about 3.5 mol % to about 6.5 mol%, or about 4 mol % to about 6 mol % total nickel relative to thesubstrate. For example, in certain embodiments, the catalyst loading isabout 3 mol %, about 4 mol %, about 5 mol %, about 6 mol %, about 7 mol%, about 8 mol %, about 9 mol %, about 10 mol %, about 11 mol %, about12 mol %, about 13 mol %, or about 14 mol % total nickel. In certainembodiments, the catalyst loading is about 2 mol %, about 2.5 mol %,about 3 mol %, about 3.5 mol %, about 4 mol %, about 4.25 mol %, about4.5 mol %, about 4.75 mol %, about 5 mol %, about 5.25 mol %, about 5.5mol %, about 5.75 mol %, about 6 mol %, about 6.5 mol %, about 7 mol %,about 7.5 mol %, about 8 mol %, about 8.5 mol %, or about 9% totalnickel.

In certain embodiments, the transition metal catalyst is present underthe conditions of the reaction from an amount of about 0.01 mol % toabout 10 mol % total palladium relative to the substrate, which is thecompound of formula (II). In certain embodiments, the catalyst loadingis from about 0.05 mol % to about 5 mol % total palladium relative tothe substrate. In certain embodiments, the catalyst loading is fromabout 0.05 mol % to about 2.5 mol %, about 0.05 mol % to about 2%, about0.05 mol % to about 1%, about 0.02 mol % to about 5 mol %, about 0.02mol % to about 2.5 mol %, about 0.02 mol % to about 1 mol %, about 0.1mol % to about 5 mol %, about 0.1 mol % to about 2.5 mol %, or about 0.1mol % to about 1 mol % total palladium relative to the substrate. Forexample, in certain embodiments, the catalyst loading is about 0.01 mol%, about 0.05 mol %, about 0.1 mol %, about 0.15 mol %, about 0.2 mol %,about 0.25 mol %, about 0.3 mol %, about 0.4 mol %, about 0.5 mol %,about 0.6 mol %, about 0.7 mol %, about 0.8 mol %, about 0.9 mol %,about 1 mol %, about 1.5 mol %, about 2 mol %, about 3 mol %, or about 5mol % total palladium.

Ligands

In certain embodiments, the methods disclosed herein use a Ni(0)catalyst comprising a chiral ligand.

In certain embodiments, the Pd (II) catalyst further comprises a chiralligand.

One aspect of the disclosure relates to the enantioselectivity of themethods. Enantioselectivity results from the use of chiral ligandsduring the acylation reaction. Without being bound by theory, theasymmetric environment that is created around the metal center by thepresence of chiral ligands produces an enantioselective reaction. Thechiral ligand forms a complex with the transition metal (e.g., nickel),thereby occupying one or more of the coordination sites on the metal andcreating an asymmetric environment around the metal center. Thiscomplexation may or may not involve the displacement of achiral ligandsalready complexed to the metal. When displacement of one or more achiralligands occurs, the displacement may proceed in a concerted fashion,i.e., with both the achiral ligand decomplexing from the metal and thechiral ligand complexing to the metal in a single step. Alternatively,the displacement may proceed in a stepwise fashion, i.e., withdecomplexing of the achiral ligand and complexing of the chiral ligandoccurring in distinct steps. Complexation of the chiral ligand to thetransition metal may be allowed to occur in situ, i.e., by admixing theligand and metal before adding the substrate. Alternatively, theligand-metal complex can be formed separately, and the complex isolatedbefore use in the alkylation reactions of the present disclosure.

Once coordinated to the transition metal center, the chiral ligandinfluences the orientation of other molecules as they interact with thetransition metal catalyst. Coordination of the metal center with an arylhalide and reaction of the substrate with the aryl halide-metal complexare dictated by the presence of the chiral ligand. The orientation ofthe reacting species determines the stereochemistry of the products.

Chiral ligands of the disclosure may be bidentate or monodentate or,alternatively, ligands with higher denticity (e.g., tridentate,tetradentate, etc.) can be used. Preferably, the ligand will besubstantially enantiopure. By “enantiopure” is meant that only a singleenantiomer is present. In many cases, substantially enantiopure ligands(e.g., ee >99%, preferably >99.5%, even more preferably >99.9%) can bepurchased from commercial sources, obtained by successiverecrystallizations of an enantioenriched substance, or by other suitablemeans for separating enantiomers.

Exemplary chiral ligands may be found in U.S. Pat. No. 7,235,698, theentirety of which is incorporated herein by reference. In certainembodiments, the chiral ligand is an enantioenriched phosphine ligand.In certain embodiments, the enantioenriched phosphine ligand is aferrocenyl ligand such as a Mandyphos-type ligand, a Josiphos-typeligand, a Taniaphos-type ligand, or a Walphos-type ligand. Preferredchiral ligands of the disclosure include a Mandyphos-type ligand or aJosiphos-type ligand. In certain embodiments, the Mandyphos-type ligandor the Josiphos-type ligand is selected from SL-M003-2, SL-M004-1,SL-M004-2, SL-M009-1, SL-M009-2, SL-J001-1, SL-J002-1, SL-J003-1,SL-J004-1, SL-J006-1, SL-J007-1, SL-J013-1, SL-J212-1, and SL-J418-1. Insome embodiments, the enantioenriched phosphine ligand is selected from(R)-BINAP, (R)-DM-BINAP, (S)-DTBM-SEGPHOS, (R)-BTFM-Garphos,(S)-C3-TunePhos, (R)-P-Phos, (2S,5S)-Me-ferocelane,(2S,5S)-Et-ferocelane, (2S,5S)-Me-f-Ketalphos, SL-M001-2, SL-M003-2,SL-M004-1, SL-M004-2, SL-M009-1, SL-M009-2, SL-J001-1, SL-J002-1,SL-J003-1, SL-J004-1, SL-J006-1, SL-J007-1, SL-J013-1, SL-J212-1,SL-J418-1, SL-W001-1, SL-W002-1, SL-W005-1, SL-W006-1, SL-W008-1,SL-W009-1, and SL-W022-1. In some embodiments, the enantioenrichedphosphine ligand is selected from (R)-BINAP, (R)-DM-BINAP,(S)-C3-TunePhos, SL-M001-2, SL-M003-2, SL-M004-1, SL-M004-2, SL-M009-1,SL-M009-2, SL-J001-1, SL-J002-1, SL-J003-1, SL-J004-1, SL-J006-1,SL-J013-1, SL-J212-1, SL-W001-1, SL-W002-1, SL-W005-1, SL-W006-1,SL-W008-1, and SL-W009-1. In some embodiments, the enantioenrichedphosphine ligand is selected from (S)-DTBM-SEGPHOS, (R)-BTFM-Garphos,(R)-P-Phos, (2S,5S)-Me-ferocelane, (2S,5S)-Et-ferocelane,(2S,5S)-Me-f-Ketalphos, SL-J007-1, SL-J418-1, and SL-W022-1. The ligandstructures are depicted in FIG. 1.

Generally, the chiral ligand is present in an amount in the range ofabout 0.1 equivalents to about 10 equivalents relative to the amount oftotal metal from the catalyst, preferably in the range of about 0.1 toabout 6 equivalents relative to the amount of total metal from thecatalyst, and most preferably in the range of about 0.5 to about 4.5equivalents relative to the amount of total metal from the catalyst.Alternatively, the amount of the chiral ligand can be measured relativeto the amount of the substrate.

In certain embodiments, the ligand is present under the conditions ofthe reaction from an amount of about 0.1 mol % to about 100 mol %relative to the substrate, which is the compound of formula (II). Theamount of ligand present in the reaction is alternatively referred toherein as “ligand loading” and is expressed as a percentage that iscalculated by dividing the moles of ligand by the moles of the substratepresent in a given reaction. In certain embodiments, the ligand loadingis from about 0.5 mol % to about 50 mol %. For example, in certainembodiments, the ligand loading is about 9 mol %, about 10 mol %, about11 mol %, about 12 mol %, about 13 mol %, about 14 mol %, or about 15mol %. In certain embodiments, the ligand is in excess of the transitionmetal catalyst. In certain embodiments, the ligand loading is about 10times the transition metal catalyst loading.

Where a chiral ligand is used, the reactions of the disclosure mayenrich the stereocenter bearing R² in the product relative to theenrichment at this center, if any, of the starting material.

In certain embodiments, the chiral ligand used in the methods of thedisclosure yields a compound of formula (I) that is enantioenriched. Thelevel of enantioenrichment of a compound may be expressed asenantiomeric excess (ee). The ee of a compound may be measured bydividing the difference in the fractions of the enantiomers by the sumof the fractions of the enantiomers. For example, if a compound is foundto comprise 98% (S)-enantiomer, and 2% (R) enantiomer, then the ee ofthe compound is (98-2)/(98+2), or 96%. In certain embodiments, thecompound of formula (I) has about 5% ee or greater, 10% ee or greater,15% ee or greater, 20% ee or greater, 25% ee or greater, 30% ee orgreater, 40% ee or greater, 50% ee or greater, 60% ee or greater, 70% eeor greater, about 80% ee, about 85% ee, about 88% ee, about 90% ee,about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee,about 96% ee, about 97% ee, about 98% ee, about 99% ee, or above about99% ee, even where this % ee is greater than the % ee of the startingmaterial, such as 0% ee (racemic). In certain embodiments, the compoundof formula (I) is enantioenriched. In certain embodiments, the compoundof formula (I) is enantiopure. In embodiments where the startingmaterial has more than one stereocenter, reactions of the disclosure mayenrich the stereocenter bearing R² relative to the enrichment at thiscenter, if any, of the starting material, and substantiallyindependently of the stereochemical disposition/enrichment (de) of anyother stereocenters of the molecule. For example, a product of themethods described herein may have 5% de or greater, 10% de or greater,15% de or greater, 20% de or greater, 25% de or greater, 30% de orgreater, 40% de or greater, 50% de or greater, 60% de or greater, 70% deor greater, 80% de or greater, 90% de or greater, 95% de or greater, oreven 98% de or greater at the stereocenter of the product bearing R².

Acylation Conditions

In certain embodiments, the methods of the disclosure include treating acompound of formula (II) with a Ni(0) catalyst comprising a chiralligand; an aryl nitrile; and an aryl halide under acylation conditions.In certain embodiments, acylation conditions further comprise a base,such as NaHMDS, KHMDS, LiHMDS, and tBuOLi. In certain embodiments, thebase is LiHMDS. In certain embodiments, acylation conditions furthercomprise a lithium salt. In certain embodiments, the lithium salt isLiBr.

In certain embodiments, acylation conditions of the reaction include oneor more organic solvents. In certain embodiments, organic solventsinclude aromatic or non-aromatic hydrocarbons, ethers, alkylacetates,nitriles, or combinations thereof. In certain embodiments, organicsolvents include hexane, pentane, benzene, toluene, xylene, cyclicethers such as optionally substituted tetrahydrofuran and dioxane,acyclic ethers such as dimethoxyethane, diethyl ether, methyl tertbutylether, and cyclopentyl methyl ether, acetonitrile, isobutyl acetate,ethyl acetate, isopropyl acetate, or combinations thereof. In certainpreferred embodiments, the solvent is toluene, tetrahydrofuran, dioxane,methyl tent-butyl ether, dimethoxyethane, or a mixture of toluene andtetrahydrofuran. In certain other preferred embodiments, the solvent isa mixture of toluene and tetrahydrofuran. In certain embodiments, themixture of toluene and tetrahydrofuran is in a ratio of 1:5, 1:2, 1:1,2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, or15:1. In certain embodiments, the mixture of toluene and tetrahydrofuranis in a ratio of 5:1 or 10:1.

In certain embodiments, acylation conditions further comprise adding anacidic solution. In certain embodiments, the acidic solution comprisesan acid selected from acetic acid, boric acid, carbonic acid, citricacid, hydrochloric acid, hydrofluoric acid, nitric acid, oxalic acid,phosphoric acid, sulfuric acid, and trifluoracetic acid. In certainembodiments, the acidic solution comprises HCl.

In certain embodiments, acylation conditions of the reaction include areaction temperature. In certain embodiments, the reaction temperatureis ambient temperature (about 20° C. to about 26° C.). In certainembodiments, the reaction temperature is higher than ambienttemperature, such as, for example, about 30° C., about 35° C., about 40°C., about 45° C., about 50° C., about 55° C., or about 60° C. Reactiontemperature may be optimized per each substrate.

In certain embodiments, instruments such as a microwave reactor may beused to accelerate the reaction time. Pressures range from atmosphericto pressures typically used in conjunction with supercritical fluids,with the preferred pressure being atmospheric.

Exemplification

The disclosure described generally herein will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present disclosure, and are not intended to limit the disclosure.

List of Abbreviations:

ee—enantiomeric excess, de—stereochemical disposition/enrichmentdr—diastereomeric ratio, HPLC—high-performance liquid, chromatography,SFC—supercritical fluid chromatography, TLC—thin-layer chromatography,AcOEt—ethyl acetate, THF—tetrahydrofuran, MeOH—methanol,MeCN—acetonitrile, IPA—isopropanol, Ni(COD)₂—Ni [(1,5-cyclooctadiene)₂], BINAP—(2,2′-bis(diphenylphosphino)-1,1ζ-binaphthyl),LiHMDS or LHMDS—lithium hexamethyldisilazide, NaHMDS—sodiumhexamethyldisilazide, KHMDS—potasium hexamethyldisilazide, lithiumtert-butoxide—tBuOLi, PMP—p-methoxyphenyl, CAN—ceric ammonium nitrate,TFA—trifluoroacetic acid, m-CPBA—m-chloroperoxybenzoic acid,

EXAMPLE 1 Discovery of Ni-Catalyzed C-Acylation

An α-acylated product (4a is produced by the reaction of the lithiumenolate derived from lactam 1a in the presence of benzonitrile (2a),chlorobenzene (3a), and a Ni(0) precatalyst (Table 1, entry 1).¹⁰Initially, we imagined that 4a could be formed by direct nucleophilicaddition of the lithium enolate of lactam 1a to benzonitrile 2a followedby hydrolysis of the resulting imine. Therefore, we conducted a seriesof control experiments to confirm the reaction pathway. Contrary to ourexpectations, in the absence of Ni(COD)₂ and BINAP the reaction did notproduce the product 4 a, and only trace amount of product was obtainedfrom the reaction in the absence of ligand (entries 2 and 3). Mostinterestingly, the reaction did not proceed without aryl chloride 3a(entry 4). Notably, Pd(0) and Ni(II) did not promote the reaction(entries 5 and 6) under these reaction conditions. Finally, as weobserved product 4a when substituting chlorotoluene for chlorobenzene inthe reaction, we elucidated that the source of the α-benzoyl grouppresent in the product is indeed benzonitrile (2a) and not thecorresponding chloroarene.

TABLE 1 Discovery of a Ni-catalyzed enolate acylation

Entry Deviation from Standard Conditions Yield [%] 1 none 99 2 NoNi(COD)₂ or (R)-BINAP 99 3 No (R)-BINAP 99 4 No PhCl 90 5 Pd(dba)₂instead of Ni(COD)₂ 99 6 NiCl₂ instead of Ni(COD)₂ 99 7 p-toluoylClinstead of PhCl 14 ^(b)) HPLC conversion.

The standard reaction conditions were lactam (1 equiv), PhCN (2 equiv),aryl chloride (2 equiv), LHMDS (1.1 equiv), Ni(COD)₂ (10 mol %), ligand(12 mol %), in 5:1 toluene-THF (0.2 M) at 23° C. for 20 h, then 1 M HClaq at 23° C. for 0.5 h.

EXAMPLE 2 Exploration of Chiral Ligand and Solvent

The C-acylation of lactam 1a using a variety of chiral ligands (12 mol%) with Ni(COD)₂ (10 mol %) and LHMDS (1.1 equiv) (Table 2) in a rangeof solvents at 23° C. (Table 3). The ligands of Table 2 are shown inFIG. 1. As a result of this study, Mandyphos-type ligands (e.g., L2 andL3) emerged as promising candidates, displaying good enantioselectivityand reactivity. Further examination revealed that a Josiphos-type ligand(i.e., L4) in TBME promotes the reaction with greater enantioselectivity(−60% ee) and conversion (74%).

General Procedure A for Ligand and Solvent Screen: To a solution ofNi(COD)₂ (1.10 mg, 4.00 μmol, 0.100 equiv) and ligand (4.80 μmol, 0.120equiv) in solvent (0.1 mL) was added a solution of lactam 1a (8.21 mg,40.0 μmol, 1.00 equiv), benzonitrile 2a (8.24 μL, 20.0 μmol, 2.00equiv), chlorobenzene 3a (8.13 μL, 20.0 μmol, 2.00 equiv) and LHMDS(7.36 mg, 44.0 λmol. 1.10 equiv) in solvent (0.1 mL) and the reactionmixture was stirred at 25° C. for 20 h. 1M HCl aqueous solution (0.5 mL)was added and the mixture was stirred at ambient temperature for 0.5 h.AcOEt (0.5 mL) was added and the mixture was stirred for 1 min. Theorganic layer (10 μL) was sampled and diluted to a mixture of hexanesand IPA (8/2, 1 mL). This solution was analyzed for conversion andenantiomeric excess (see Methods for the Determination of EnantiomericExcess).

TABLE 2 Assessment of the chiral ligand for the lactam acylation.

Entry Ligand Conversion [%] ee [%]  1 (R)-BINAP 31 7  2 (R)-T-BINAP 61 3 3 (R)-DM-BINAP 87 7  4 (R)-H8-BINAP 73 −2  5 (R)-SEGPHOS 1 −31  6(R)-DM-SEGPHOS 59 −1  7 (R)-DTBM-SEGPHOS 26 −32  8 (R)-DIFLUORPHOS 2 8 9 (S)-Xyl-MeBIHEP 66 2 10 (R)-BTFM-Garphos 22 −10 11 (R)-SYNPHOS 45 −112 (R)-SOLPHOS 33 −3 13 (S)-C₃-TunePhos 53 6 14 (R)-P-Phos 19 −5 15(R)-Phanephos 15 −2 16 (R)-SDP 16 3 17 (S)-Monophos 74 1 18 (S)-BINAPINE8 11 19 CatASiumMN Xyl (R) 4 13 20 CatASiumMN Xyl^(F) (R) 6 2 21(R,R)-Chiraphos 0 — 22 (R, R)-DIOP 0 — 23 (2S,5S)-MeBPE 0 — 24(2R,5R)-MeDUPHOS 0 — 25 (R)-MOP 0 — 26 (R)-QUINAP 0 — 27 DATCH-Phenyl 0— 28 (S)-tBuPHOX 2 10 29 (S)-tBu-Mebox 0 — 30 (S)-iPr-ptbox 0 — 31tangphos 3 7 32 (2S,5S)-Me-Ferocelane 76 −24 33 (2S,5S)-Et-Ferocelane 25−6 34 (2S,5S)-iPr-Ferocelane 1 35 35 (2S,5S)-Me-f-Ketalphos 63 −56 36SL-J001-1 80 16 37 SL-J002-1 53 13 38 SL-J003-1 41 5 39 SL-J004-1 54 840 SL-J005-1 7 −8 41 SL-J006-1 79 30 42 SL-J007-1 85 −6 43 SL-J008-1 18−1 44 SL-J009-1 5 1 45 SL-J013-1 32 10 46 SL-J015-1 5 2 47 SL-J212-1 8612 48 SL-J216-1 4 −5 49 SL-J404-1 37 1 50 SL-J418-1 44 −12 51 SL-J502-14 −4 52 SL-J505-1 0 — 53 SL-W001-1 52 20 54 SL-W002-1 64 10 55 SL-W003-19 −16 56 SL-W005-1 54 14 57 SL-W006-1 61 18 58 SL-W008-1 19 16 59SL-W009-1 64 7 60 SL-W022-1 7 −14 61 SL-M001-2 39 35 62 SL-M002-2 0 — 63SL-M003-2 25 15 64 SL-M004-2 70 59 65 SL-M009-2 71 62 66 SL-M012-2 0 —67 SL-T001-1 7 34 68 SL-T002-1 0 — 69 Chenphos 0 —

Shown above is the scheme for the chiral ligand and solvent screen ofTable 3.

TABLE 3 Assessment of the chiral ligand and solvent for the lactamacylation. Conversion ee Entry Ligand Solvent [%] ^(a)) [%] ^(b)) 1 L1,(R)-BINAP Toluene 31 7 2 L2, SL-M004-1 Toluene 70 59 3 L2, SL-M004-1 THF32 15 4 L2, SL-M004-1 Dioxane 52 47 5 L2, SL-M004-1 TBME 72 51 6 L2,SL-M004-1 DME 53 25 7 L2, SL-M004-1 Toluene-THF (5:1) 53 52 8 SL-M004-2Toluene 70 59 9 SL-M004-2 THF 32 15 10 SL-M004-2 Dioxane 52 47 11SL-M004-2 TBME 72 51 12 SL-M004-2 DME 53 25 13 SL-M004-2 Toluene-THF(5:1) 53 52 14 L3, SL-M009-1 Toluene 71 62 15 L3, SL-M009-1 THF 29 13 16L3, SL-M009-1 Dioxane 42 47 17 L3, SL-M009-1 TBME 42 31 18 L3, SL-M009-1DME 47 21 19 L3, SL-M009-1 Toluene-THF (5:1) 45 53 20 SL-M009-2 Toluene71 62 21 SL-M009-2 THF 29 13 22 SL-M009-2 Dioxane 42 47 23 SL-M009-2TBME 42 61 24 SL-M009-2 DME 47 21 25 SL-M009-2 Toluene-THF (5:1) 45 5326 SL-M009-2 Methylcyclohexane 48 13 27 SL-M009-2 nBu₂O 0 — 28 SL-M009-2DMF 0 — 29 L4, SL-J006-1 Toluene 79 30 30 L4, SL-J006-1 THF 26 2 31 L4,SL-J006-1 Dioxane 52 30 32 L4, SL-J006-1 TBME 74 60 33 L4, SL-J006-1 DME37 6 34 L4, SL-J006-1 Toluene-THF (5:1) 54 41 35 L4, SL-J006-1Methylcyclohexane 96 25 36 L4, SL-J006-1 nBu₂O 0 — 37 L4, SL-J006-1 DMF0 —

EXAMPLE 3 Exploration of Bases, Aryl Halides, and Additives

Further studies aimed toward optimization of bases, aryl halides, andadditives are summarized in Table 4. Surprisingly, no enantioselectivitywas observed in reactions using NaHMDS or KHMDS instead of LHMDS(entries 2-4), indicating that lithium cations are essential forenantioselectivity. Bromobenzene (3b) exhibited superiorenantioselectivity and reactivity compared to chlorobenzene (3a, cf.entries 2 and 5), iodobenzene (3c, cf. entries 6 and 5), and phenyltriflate (3d, cf. entries 7 and 5). Encouraged by these results, weexamined lithium salt additives. To our delight, reactivity andenantioselectivity were improved dramatically by adding LiBr, especiallyusing the Mandyphos-type ligands (entries 9 and 10). It is conceivablethat the size and Lewis acidity of the lithium cation is well suited tocoordinate the dimethyl amino groups on the Mandyphos-type ligand in aproductive manner (cf entries 9 and 10 vs. 11).

TABLE 4 Assessment of bases, aryl halides, and additives for the lactamacylation.

Conversion ee Entry Ligand Base PhX Solvent Additive [%] [%] 1 L4 tBuOLiPhCl 3a TBME — 0 — 2 L4 LHMDS PhCl 3a TBME — 74 −54 3 L4 NaHMDS PhCl 3aTBME — 42 — 4 L4 KHMDS PhCl 3a TBME — 51 — 5 L4 LHMDS PhBr 3b TBME — 83−61 6 L4 LHMDS PhI 3c TBME — 65 −55 7 L4 LHMDS PhOTf 3d TBME — 73 −28 8L2 LHMDS PhBr 3b Toluene-THF 10:1 — 55 68 9 L2 LHMDS PhBr 3b Toluene-THF10:1 LiBr 98 89 10 L3 LHMDS PhBr 3b Toluene-THF 10:1 LiBr 92 89 11 L4LHMDS PhBr 3b Toluene-THF 10:1 LiBr 28 −46

The lactams 4 a of entries 1-7 were prepared according to the generalprocedure A with lactam (1 equiv), PhCN (2 equiv), PhX (2 equiv), base(1.1 equiv), Ni(COD)₂ (10 mol %), ligand (12 mol %), in TBME (0.2 M) at23° C. for 20 h, then 1 M HCl aq at 23° C. for 0.5 h. The lactams 4 aofentries 8-11 were prepared according to the general procedure A withlactam (2 equiv), PhCN (1 equiv), PhX (1 equiv), base (1.2 equiv),Ni(COD)₂ (10 mol %), ligand (12 mol %), in toluene-THF (10:1) (0.2 M) at23° C. for 20 h, then 1 M HCl aq. 0.5 h at 23° C.

EXAMPLE 4 Survey of the N-Protecting Group

The effect of substituents on the N-aryl fragment of the lactamsubstrate was examined.

Several lactams (1a-d) were prepared and subjected to the optimizedacylation conditions (Table 5). Lactam 1b displayed slightly superiorenantioselectivity to 1a, although acylated product 4b was produced inmoderate yield at ambient temperature. Gratifyingly, reaction at 0° C.led to improved yield of lactam 4b. Derivatives 1c and 1d had similarenantioselectivity as the parent PMP-lactam 1a. In general, a fairamount of substitution around the N-aryl group is tolerated in thereaction process affording acylated lactams in good yields and with highee.

Conversion of allyl 1-methyl-2-oxocyclohexane-carboxylate (1a) in TBMEresulted in a high yield and good enantioselectivity (Table 4, entry 1).When the reaction was performed in various alkyl acetates the yieldsdropped dramatically, to 12%, 28% and 17% respectively (Table 4, entries2, 4 and 5). Similarly low yields were observed for reactions performedin acetonitrile, dimethylacetamide, 2-Me-THF, and acetone (Table 4,entries 3, 6, 8 and 10). Moderate conversion was found when the reactionwas performed in toluene (Table 4, entry 7). Consequently, all furtherexperiments were carried out in TBME.

TABLE 5 Survey of the N-protecting group for the lactam acylation.

R yield, ee

1a→4a 86%, 88% ee^(b)

1b→4b

1d→4d 61%, 92% ee^(b) 1c→4c 69%, 86% ee^(c) 81%, 92% ee^(c) 80%, 95%ee^(c) aConditions: lactam (2 equiv), PhCN (1 equiv), PhBr (1.5 equiv),LHMDS (1.2 equiv), LiBr (5 equiv), Ni(COD)₂ (10 mol %), ligand (12 mol%), in toluene-THF (10:1, 0.09M), then 1M HCl aq. ^(b)Reactions wereconducted at 23° C. for 24 h. ^(c)Reactions were conducted at 0° C. for48 h.

EXAMPLE 5 Survey of the Substrate

The substrate scope of this enantioselective C-acylation reaction wasexplored (Tables 6 and 6). Generally, the process is tolerant of a widerange of substituents and functionality on both the aryl nitrile and theparent lactam substrate. Aryl nitriles having both electron-donating andelectron-withdrawing substituents at the para position can besuccessfully applied, leading to products with excellentenantioselectivities (e.g., Table 6, 6, 9-12). Despite the uniformlyhigh ee, electron-withdrawing substituents on the nitrile furnishproducts in significantly diminished yields (e.g., 11, 12). Lastly, thereaction is not impacted to a large degree when the nitrile issubstituted at either the meta or ortho position (e.g., 7, 8).

TABLE 6 Assessment of the nitrile for the lactam acylation.

products

4b 81% yield, 92% ee

6 92% yield, 91% ee

7 91% yield, 93% ee

8 69% yield, 94% ee

9 89% yield, 92% ee

10 85% yield, 89% ee

11 36% yield, 94% ee

12 23% yield, 87% ee^(b)

13 66% yield, 91% ee ^(a)Conditions: lactam (2 equiv), ArCN (1 equiv),PhBr (1.5 equiv), base (1.2 equiv), Ni(COD)₂ (10 mol %), ligand (12 mol%), in toluene-THF (10:1, 0.09M) at 0° C. for 48 h, then 1M HCl aq.^(b)The reaction was carried out at 23° C. for 24 h.

The scope of substitution at the lactam α-carbon is illustrated in Table7. Although the enantioselectivity tends to decrease with largerα-substituents, examples having ethyl, benzyl, substituted-benzyl andsubstituted-allyl groups all furnished the C-acylated products with goodenantioselectivities (74-88% ee). Crotyl- and cinnamyl-substitutedlactams were particularly effective in the acylation, providinginteresting lactam products in high ee (e.g., 21-25).

TABLE 7 Assessment of the lactam α-substituent for the lactam acylation.

products^(a)

14 50% yield, 77% ee

15 (R = H): 61% yield, 81% ee 16 (R = OMe): 77% yield, 81% ee 17 (R =F): 76% yield, 74% ee

18 58% yield, 71% ee

19 67% yield, 60% ee

20 71% yield, 76% ee

21 70% yield, 86% ee

22 (R = H): 50% yield, 86% ee 23 (R = Me): 85% yield, 88% ee 24 (R =OMe): 68% yield, 88% ee 25 (R = F): 62% yield, 83% ee

26 76% yield, 83% ee

27 35% yield, 84% ee

The lactams 14-27 were prepared according to the general procedure Awith lactam (2 equiv), p-tolunitrile (1 equiv), PhBr (1.5 equiv), base(1.2 equiv), Ni(COD)₂ (10 mol %), ligand (12 mol %), in toluene-THF(10:1, 0.09 M) at 0° C. for 48 h, then 1 M HCl aq.

EXAMPLE 6 Derivatization of C-Acylated Products and Determination ofAbsolute Stereochemistry

To demonstrate the synthetic utility of our enantioselective lactamsacylation, transformations were carried out on the enantioenrichedlactam products generated in this disclosure (Scheme 1). The o-methoxyprotecting group of lactam 4e was easily removed by CAN oxidation toform lactam 28 (Scheme 1A).¹¹ Reduction of ketone 4e with Et₃SiHproceeded with perfect diastereoselectively and afforded alcohol 29 as asingle isomer in excellent yield (Scheme 1B). The relativestereochemistry of lactam 29 was determined by single crystal X-raydiffraction (data not shown). Lactam 4a could be converted toα-benzoyloxy lactam 30 by Baeyer-Villiger oxidation, without loss ofenantiopurity (Scheme 1C). Alternatively, Baeyer-Villiger oxidation oflactam 10 gave α-aryloxycarbonyl lactam 31 (Scheme 1D). The PMP ketonedirects the regioselectivity of the Baeyer-Villiger oxidation and allowsfor the asymmetric synthesis of α-carboxy lactam derivatives.¹² Todetermine the absolute stereochemistry, 31 was converted to known lactamderivative 33 by ester exchange followed by deprotection of theo-methoxyphenyl group. The specific optical rotation of carboxylactam 33corresponded to the reported value for (R)-33.¹³ The absoluteconfigurations of all acylated lactam products disclosed herein arepresented by analogy to this finding.

EXAMPLE 6 Possible Reaction Mechanism of C-Acylation of Lactams

By avoiding an acidic aqueous work-up and carefully chromatographing ofthe crude reaction mixture, imine 34 was obtained as a 60:40 E/Z mixturefrom the reaction of lactam 1a with o-tolunitrile 2b and bromobenzene 3b(Scheme 2A). Additionally, amine 36 as a 63:37 diastereomeric mixturewas prepared by in situ reduction of imine intermediate 35 (Scheme 2B).These experiments provide evidence that an N-arylated imine (e.g., 5a,34, and 35) may be the direct product of the catalytic reaction.

A possible reaction mechanism for the disclosed C-acylation reaction isshown in FIG. 2. Without being bound by theory, the reaction may proceedby a Ni⁰/Ni^(II) redox catalytic cycle. Oxidative addition of the arylbromide to a Ni⁰ complex (i.e., A) produces a Ni^(II) arene species (B).Ligand substitution and insertion of the benzonitrile and lactam enolateis envisioned to be stereodetermining and to produce Ni^(ee)-iminocomplex C. Reductive elimination from C leads to the primary imineproduct and regenerates Ni⁰ complex A . The C-acylated product isultimately furnished by hydrolysis of the imine in aqueous acid.

EXAMPLE 7 Experimental Procedures General Procedure for α-SubstitutedLactam Substrates

General Procedure 1:1-(2-methoxyphenyl)pyrrolidin-2-one (SI2)

To a suspension of lactam SI1 (8.17 g, 96.0 mmol, 1.20 equiv), K₂CO₃(22.1 g, 160 mmol, 2.00 equiv) and CuI (1.52 g, 8.00 mmol, 0.10 equiv)in toluene (80 mL) were added 2-bromoanisole (9.84 mL, 80.0 mmol, 1.00equiv) and N,N′-dimethylethylendiamine (1.68 mL, 16.0 mmol, 0.20 equiv).The reaction mixture was stirred at 100° C. for 18 h then allowed tocool to ambient temperature and filtered through a pad of silica geleluting with AcOEt (250 mL). The eluate was concentrated under reducedpressure and the residue was purified by flash column chromatography(1:1 EtOAc:hexanes) on silica gel to give lactam SI2 as a pale yellowoil (9.88 g, 65% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.35-7.26 (m, 2H),7.06-6.97 (m, 2H), 3.88 (s, 3H), 3.80 (t, J=7.0 Hz, 2H), 2.60 (t, J=8.1Hz, 2H), 2.23 (p, J=7.5 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 175.2,154.8, 128.7, 128.6, 127.2, 120.9, 112.0, 55.6, 49.9, 31.2, 19.0; IR(Neat Film NaCl) 2968, 2889, 2838, 1694, 1504, 1461, 1408, 1304, 1281,1253, 1023, 755 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₁H₁₄NO₂[M+H]⁺: 192.1019, found 192.1019.

General Procedure 2: 1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one (1b)

To a solution of diisopropylamine (3.07 mL, 22.0 mmol, 1.10 equiv) inTHF (17 mL) was added a solution of n-BuLi (8.80 mL, 22.0 mmol, 2.5 M inhexanes, 1.10 equiv) dropwise at −78° C. After 20 min at −78° C., asolution of lactam SI2 (3.82 g, 20.0 mmol, 1.00 equiv) in THF (50 mL)was added dropwise. After an additional 20 min, a solution of methyliodide (15.0 mL, 30.0 mmol, 2.0 M in TBME, 1.50 equiv) was added and thereaction mixture was stirred at −78° C. for 3 h. Saturated NH₄Cl aqueoussolution (50 mL) was added and the mixture was allowed to ambienttemperature. The mixture was extracted with AcOEt (100 mL), washed withbrine (30 mL), dried over Na₂SO_(4,) and concentrated under reducedpressure. The residue was purified by flash column chromatography (1:4to 1:2 EtOAc:hexanes) on silica gel to give lactam 1b as a white solid(2.86 g, 70% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.26 (m, 3H),7.06-6.96 (m, 2H), 3.87 (s, 3H), 3.79-3.66 (m, 2H), 2.69 (tq, J=8.7, 7.1Hz, 1H), 2.41 (dddd, J=12.2, 8.5, 7.3, 3.5 Hz, 1H), 1.86 (dq, J=12.4,8.5 Hz, 1H), 1.36 (d, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.5,154.8, 128.6, 128.5, 127.6, 120.8, 112.0, 55.6, 47.9, 36.9, 28.1, 16.3;IR (Neat Film NaCl) 2965, 2932, 2874, 1695, 1504, 1463, 1456, 1403,1311, 1296, 1277, 1251, 1024, 754 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'dfor C₁₂H₁₆NO₂ [M+H]⁺: 206.1176, found 206.1176.

N-Protected Lactams 1-(4-Methoxyphenyl)pyrrolidin-2-one (SI3)

Lactam SI3 was prepared according to the general procedure 1, using4-iodoanisole and K₃PO₄ in place of 2-bromoanisole and K₂CO₃respectively, and isolated by recrystallization in hexanes/AcOEt (4/1)as a white crystal. 89% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.64-7.45 (m,2H), 7.01-6.90 (m, 2H), 3.87 (t, J=7.0 Hz, 2H), 3.84 (s, 3H), 2.64 (t,J=8.1 Hz, 2H), 2.20 (tt, J=15.1, 7.5 Hz, 1H); ¹³C NMR (126 MHz, cdcl₃) δ173.9, 156.5, 132.6, 121.8, 114.0, 55.5, 49.2, 32.5, 18.1; IR (Neat FilmNaCl) 2952, 2907, 1683, 1517, 1255, 1226, 1182, 1126, 1032, 829 cm⁻¹;HRMS (MM: ESI-APCI+) m/z calc'd for C₁₁H₁₄NO₂ [M+H]⁺: 192.1019, found192.1021.

1-(3,5-Dimethoxyphenyl)pyrrolidin-2-one (SI4)

Lactam SI4 was prepared according to the general procedure 1, using1-bromo-3,5-dimethoxybenzene in place of 2-bromoanisole, and isolated byrecrystallization in hexanes/AcOEt (5/1) as a white crystal. 89% yield.¹H NMR (500 MHz, CDCl₃) δ 6.90 (d, J=2.2 Hz, 2H), 6.31 (t, J=2.2 Hz,1H), 3.87 (t, J=7.0 Hz, 2H), 3.84 (s, 6H), 2.65 (t, J=8.1 Hz, 2H), 2.19(p, J=7.5 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 174.4, 160.8, 141.2, 98.4,96.5, 77.3, 77.0, 76.8, 55.4, 49.0, 33.1, 17.9; IR (Neat Film NaCl)2959, 1694, 1593, 1474, 1455, 1424, 1397, 1276, 1245, 1198, 1152, 1071,1056, 922, 840, 825, 683 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₁₂H₁₆NO₃ [M+H]⁺: 222.1125, found 222.1129.

1-(2-Isopropoxyphenyl)-pyrrolidin-2-one (SI5)

Lactam SI5 was prepared according to the general procedure 1, using1-bromo-2-isopropoxybenzene in place of 2-bromoanisole, and isolated byflash column chromatography (1:2 to 1:1 EtOAc:hexanes) on silica gel asa pale yellow oil. 57% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.33-7.23 (m,2H), 7.03-6.96 (m, 2H), 4.58 (hept, J=6.0 Hz, 1H), 3.82 (t, J=6.7 Hz,2H), 2.59 (t, J=7.6 Hz, 2H), 2.28-2.16 (m, 2H), 1.38 (d, J=6.0 Hz, 6H);¹³C NMR (126 MHz, CDCl₃) δ 175.2, 153.1, 128.9, 128.4, 128.4, 120.8,114.7, 70.8, 49.9, 31.4, 22.2, 19.2; IR (Neat Film NaCl) 2976, 2933,1697, 1595, 1500, 1456, 1405, 1385, 1304, 1282, 1251, 1125, 1111, 957,753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₃H₁₈NO₂ [M+H]⁺:220.1332, found 220.1328.

α-Substituted Lactams 1-(4-Methoxyphenyl)-3-methylpyrrolidin-2-one (1a)

Lactam 1a was prepared according to the general procedure 2 from SI3 inplace of SI2, and isolated by flash column chromatography (1:3EtOAc:hexanes) on silica gel as a white solid. 82% yield. ¹H NMR (500MHz, CDCl₃) δ 7.64-7.45 (m, 2H), 7.01-6.90 (m, 2H), 3.87 (t, J=7.0 Hz,2H), 3.84 (s, 3H), 2.64 (t, J=8.1 Hz, 2H), 2.20 (tt, J=15.1, 7.5 Hz,1H); ¹³C NMR (126 MHz, cdcl₃) δ 176.3, 156.4, 133.0, 121.4, 114.0, 55.5,46.9, 38.1, 27.1, 16.3; IR (Neat Film NaCl) 2952, 2882, 2835, 1682,1516, 1251, 1225, 1122, 1099, 1030, 829 cm⁻¹; HRMS (MM: ESI-APCI+) m/zcalc'd for C₁₂H₁₆NO₂ [M+H]⁺: 206.1176, found 206.1177.

1-(3,5-Dimethoxyphenyl)-3-methylpyrrolidin-2-one (1c)

Lactam 1c was prepared according to the general procedure 2 from SI4 inplace of SI2, and isolated by flash column chromatography (1:4EtOAc:hexanes) on silica gel as a white solid. 87% yield. ¹H NMR (500MHz, CDCl₃) δ 6.96 (d, J=2.2 Hz, 2H), 6.31 (t, J=2.2 Hz, 1H), 3.84 (s,6H), 3.79 (dd, J=8.8, 5.0 Hz, 2H), 2.78-2.66 (m, 1H), 2.45-2.35 (m, 1H),1.86-1.74 (m, 1H), 1.35 (d, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ176.9, 160.8, 141.5, 97.9, 96.5, 77.3, 77.0, 76.8, 55.4, 46.8, 38.6,26.9, 16.1; IR (Neat Film NaCl) 2964, 1698, 1597, 1474, 1392, 1273,1246, 1208, 1154, 1071, 927, 834, 682 cm⁻¹; HRMS (MM: ESI-APCI+) m/zcalc'd for C₁₃H₁₈NO₃ [M+H]⁺: 236.1281, found 236.1284.

1-(2-Isoproxyphenyl)-3-methylpyrrolidin-2-one (1d)

Lactam 1d was prepared according to the general procedure 2 from SI5 inplace of SI2, and isolated by flash column chromatography (1:3 to 1:2EtOAc:hexanes) on silica gel as a pale yellow oil. 83% yield. ¹H NMR(500 MHz, CDCl₃) δ 7.32-7.22 (m, 2H), 7.03-6.96 (m, 2H), 4.57 (hept,J=6.1 Hz, 1H), 3.80-3.67 (m, 2H), 2.67 (tq, J=8.4, 7.1 Hz, 1H),2.46-2.35 (m, 1H), 1.84 (dq, J=12.3, 8.2 Hz, 1H), 1.37 (d, J=6.1 Hz,6H), 1.35 (d, J=7.2 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.5, 153.2,129.0, 128.7, 128.3, 120.8, 114.8, 70.8, 47.9, 36.9, 28.2, 22.2, 22.2,16.4; IR (Neat Film NaCl) 2974, 2930, 1701, 1595, 1499, 1457, 1405,1277, 1249, 1124, 1111, 955, 750 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'dfor C₁₄H₂₀NO₂ [M+H]⁺: 234.1489, found 234.1482.

1-(2-Methoxyphenyl)-3-ethypyrrolidin-2-one (SI6)

Lactam SI6 was prepared according to the general procedure 2 using ethyliodide in place of methyl iodide, and isolated by flash columnchromatography (1:3 EtOAc:hexanes) on silica gel as a pale yellow oil.81% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.29-7.19 (m, 2H), 7.01-6.92 (m,2H), 3.82 (s, 3H), 3.76-3.69 (m, 1H), 3.69-3.60 (m, 1H), 2.53 (qd,J=8.7, 4.3 Hz, 1H), 2.38-2.27 (m, 1H), 2.04-1.92 (m, 1H), 1.92-1.81 (m,1H), 1.63-1.49 (m, 1H), 1.04 (t, J=7.4 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)δ 176.9, 154.8, 128.7, 128.5, 127.5, 120.8, 112.0, 55.6, 48.2, 43.4,25.1, 24.2, 11.5; IR (Neat Film NaCl) 2961, 1695, 1596, 1505, 1462,1404, 1280, 1249, 1024, 752 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₁₃H₁₈NO₂ [M+H]⁺: 220.1332, found 220.1334.

3-Benzyl-1-(2-methoxyphenyl)pyrrolidin-2-one (SI7)

Lactam SI7 was prepared according to the general procedure 2 usingbenzyl bromide in place of methyl iodide, and isolated by flash columnchromatography (1:5 EtOAc:hexanes) on silica gel as a pale yellow oil.80% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.44-7.08 (m, 7H), 6.99-6.90 (m,2H), 3.80 (s, 3H), 3.63 (dt, J=9.5, 7.7 Hz, 1H), 3.49 (ddd, J=9.5, 8.6,3.7 Hz, 1H), 3.30 (dd, J=13.7, 4.0 Hz, 1H), 2.93-2.83 (m, 1H), 2.77 (dd,J=13.6, 9.7 Hz, 1H), 2.20-2.10 (m, 1H), 1.94-1.83 (m, 1H); ¹³C NMR (126MHz, CDCl₃) δ 176.0, 154.8, 139.7, 129.1, 128.6, 128.5, 128.5, 128.4,127.4, 126.3, 120.9, 112.0, 55.6, 48.0, 43.8, 37.0, 25.1; IR (Neat FilmNaCl) 2942, 1694, 1596, 1504, 1454, 1407, 1279, 1252, 1025, 753, 701 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₈H₂₀NO₂ [M+H]⁺: 282.1489,found 282.1491.

3-(4-Methoxybenzyl)-1-(2-methoxyphenyl)pyrrolidin-2-one (SI8)

Lactam SI8 was prepared according to the general procedure 2 using4-methoxybenzyl chloride in place of methyl iodide, and isolated byflash column chromatography (1:3 EtOAc:hexanes) on silica gel as a paleyellow oil. 59% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.29-7.24 (m, 1H),7.24-7.14 (m, 3H), 7.00-6.90 (m, 2H), 6.88-6.80 (m, 2H), 3.79 (s, 3H),3.78 (s, 3H), 3.62 (dt, J=9.5, 7.6 Hz, 1H), 3.47 (ddd, J=9.5, 8.6, 3.8Hz, 1H), 3.21 (dd, J=13.7, 4.0 Hz, 1H), 2.90-2.80 (m, 1H), 2.74 (dd,J=13.8, 9.4 Hz, 1H), 2.20-2.09 (m, 1H), 1.93-1.81 (m, 1H); ¹³C NMR (126MHz, CDCl₃) δ 176.1, 158.1, 154.8, 131.6, 130.1, 128.6, 128.5, 127.4,120.8, 113.8, 112.1, 55.6, 55.3, 48.1, 43.9, 36.0, 25.0; IR (Neat FilmNaCl) 2936, 1696, 1596, 1512, 11506, 1462, 1406, 1300, 1279, 1249, 1179,1028, 753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₉H₂₂NO₃ [M+H]⁺:312.1594, found 312.1589.

3-(4-Fluorobenzyl)-1-(2-methoxyphenyl)pyrrolidin-2-one (S19)

Lactam SI9 was prepared according to the general procedure 2 using4-fluorobenzyl bromide in place of methyl iodide, and isolated by flashcolumn chromatography (1:3 to 1:2 EtOAc:hexanes) on silica gel as a paleyellow oil. 77% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.18 (m, 4H),7.04-6.92 (m, 4H), 3.81 (s, 3H), 3.65 (dt, J=9.6, 7.7 Hz, 1H), 3.50(ddd, J=9.5, 8.6, 3.6 Hz, 1H), 3.24 (dd, J=13.5, 3.8 Hz, 1H), 2.93-2.76(m, 2H), 2.22-2.12 (m, 1H), 1.94-1.82 (m, 1H); ¹³C NMR (126 MHz, CDCl₃)δ 175.7, 162.6, 160.6, 154.8, 135.2, 135.1, 130.6, 130.6, 128.6, 128.5,127.3, 120.9, 115.3, 115.1, 112.0, 55.6, 48.0, 43.7, 36.1, 24.9; IR(Neat Film NaCl) 2942, 1696, 1597, 1507, 1459, 1406, 1252, 1221, 1158,1025, 752 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₈H₁₉FNO₂ [M+H]⁺:300.1394, found 300.1390.

1-(2-Methoxyphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidin-2-one (SI10)

Lactam SI10 was prepared according to the general procedure 2 using2-trifluoroethyl iodide in place of methyl iodide, and isolated by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel as a yellow oil.36% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.29 (ddd, J=8.2, 7.5, 1.7 Hz, 1H),7.23 (dd, J=7.7, 1.7 Hz, 1H), 7.03-6.93 (m, 2H), 3.83 (s, 3H), 3.80-3.72(m, 1H), 3.65 (ddd, J=9.7, 8.8, 1.6 Hz, 1H), 3.04-2.93 (m, 1H),2.93-2.84 (m, 1H), 2.56-2.46 (m, 1H), 2.14 (s, 1H), 2.07-1.95 (m, 1H);¹³C NMR (126 MHz, CDCl₃) δ 173.8, 154.7, 128.9, 128.5, 128.1, 126.8,125.9, 120.9, 112.0, 55.6, 48.0, 37.0, 36.9, 35.9, 35.7, 35.4, 35.2,26.8; IR (Neat Film NaCl) 2946, 1703, 1597, 1505, 1462, 1414, 1282,1252, 1135, 1039, 753, 615 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₁₃H₁₅F₃NO₂ [M+H]⁺: 274.1049, found 274.1049.

3-(3-(Benzyloxy)propyl)-1-(2-methoxyphenyl)pyrrolidin-2-one (SI11)

Lactam SI11 was prepared according to the general procedure 2 using((3-bromopropoxy)methyObenzene¹⁴ in place of methyl iodide, and isolatedby flash column chromatography (1:3 to 1:2 EtOAc:hexanes) on silica gelas a pale yellow oil. 76% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.18 (m,7H), 6.99-6.90 (m, 2H), 4.50 (s, 2H), 3.80 (s, 3H), 3.73-3.64 (m, 1H),3.64-3.58 (m, 1H), 3.58-3.46 (m, 2H), 2.63-2.53 (m, 1H), 2.36-2.25 (m,1H), 2.05-1.94 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.68 (m, 2H), 1.64-1.52(m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.7, 154.8, 138.6, 128.6, 128.5,128.4, 127.7, 127.5, 127.4, 120.8, 112.0, 73.0, 70.4, 55.6, 48.2, 41.8,28.0, 27.5, 25.8; IR (Neat Film NaCl) 2939, 2860, 1697, 1596, 1504,1454, 1405, 1279, 1252, 1102, 1026, 749, 699 cm⁻¹; HRMS (MM: ESI-APCI+)m/z calc'd for C₂₁H₂₆NO₃ [M+H]⁺: 340.1907, found 340.1915.

1-(2-Methoxyphenyl)-3-(3-methylbut-2-en-1-yl)pyrrolidin-2-one (SI12)

Lactam SI12 was prepared according to the general procedure 2 using1-bromo-3-methyl-2-butene in place of methyl iodide, and isolated byflash column chromatography (1:3 EtOAc:hexanes) on silica gel as a paleyellow oil. 75% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.30-7.20 (m, 2H),7.01-6.92 (m, 2H), 5.24-5.16 (m, 1H), 3.83 (s, 3H), 3.73-3.59 (m, 2H),2.69-2.53 (m, 2H), 2.33-2.22 (m, 2H), 1.91-1.80 (m, 1H), 1.74 (s, 3H),1.67 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 176.6, 154.8, 133.6, 128.6,128.5, 127.6, 121.3, 120.8, 112.0, 55.6, 55.6, 48.2, 42.3, 29.5, 25.9,25.9, 25.1, 18.0; IR (Neat Film NaCl) 2913, 1698, 1596, 1505, 1459,1405, 1279, 1252, 1025, 751 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₁₆H₂₂NO₂ [M+H]⁺: 260.1645, found 260.1644.

(E)-3-(But-2-en-1-yl)-1-(2-methoxyphenyl)pyrrolidin-2-one (SI13)

Lactam SI13 was prepared according to the general procedure 2 using1-bromo-2-butene¹⁵ in place of methyl iodide, and isolated by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel as a pale yellowoil. 24% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.30-7.21 (m, 2H), 7.01-6.92(m, 2H), 5.62-5.43 (m, 2H), 3.83 (s, 3H), 3.73-3.58 (m, 2H), 2.68-2.53(m, 2H), 2.32-2.19 (m, 2H), 1.95-1.82 (m, 1H), 1.72-1.66 (m, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 176.5, 154.8, 128.6, 128.6, 128.6, 128.1, 127.4,120.9, 112.1, 55.6, 48.2, 42.0, 34.3, 24.8, 18.1; IR (Neat Film NaCl)2937, 1699, 1596, 1505, 1456, 1436, 1404, 1298, 1279, 1252, 1107, 1046,1025, 968, 751 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₅H₂₀NO₂[M+H]⁺: 246.1489, found 246.1487.

(E)-3-Cinnamyl-1-(2-methoxyphenyl)pyrrolidin-2-one (SI14)

Lactam SI14 was prepared according to the general procedure 2 usingcinnamyl bromide in place of methyl iodide, and isolated by flash columnchromatography (1:5 to 1:2 EtOAc:hexanes) on silica gel as a pale yellowoil. 80% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.41-7.36 (m, 2H), 7.36-7.17(m, 5H), 7.02-6.93 (m, 2H), 6.51 (d, J=15.7 Hz, 1H), 6.29 (dt, J=15.7,7.1 Hz, 1H), 3.81 (s, 3H), 3.75-3.61 (m, 2H), 2.84-2.73 (m, 2H),2.57-2.46 (m, 1H), 2.38-2.27 (m, 1H), 2.03-1.92 (m, 1H); ¹³C NMR (126MHz, CDCl₃) δ 176.0, 154.8, 137.5, 132.2, 128.6, 128.6, 128.5, 127.5,127.4, 127.1, 126.1, 120.9, 112.0, 55.6, 48.2, 41.9, 34.7, 24.8; IR(Neat Film NaCl) 2941, 1694, 1596, 1504, 1463, 1407, 1253, 1025, 967,749, 694 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₀H₂₂NO₂ [M+H]⁺:308.1645, found 308.1645.

(E)-1-(2-Methoxyphenyl)-3-(3-(p-tolyl)allyl)pyrrolidin-2-one (SI15)

Lactam SITS was prepared according to the general procedure 2 using(E)-1-(3-chloroprop-1-en-1-yl)-4-methylbenzene¹⁶ in place of methyliodide, and isolated by flash column chromatography (1:3 EtOAc:hexanes)on silica gel as a pale yellow oil. 90% yield. ¹H NMR (500 MHz, CDCl₃) δ7.34-7.21 (m, 4H), 7.13 (d, J=7.9 Hz, 2H), 7.03-6.94 (m, 2H), 6.49 (d,J=15.7 Hz, 1H), 6.24 (dt, J=15.8, 7.1 Hz, 1H), 3.83 (s, 3H), 3.77-3.62(m, 2H), 2.84-2.73 (m, 2H), 2.58-2.44 (m, 1H), 2.40-2.27 (m, 4H),2.04-1.92 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 154.8, 136.9,134.7, 132.0, 129.2, 128.6, 128.6, 127.4, 126.4, 126.0, 120.9, 112.0,55.6, 48.2, 41.9, 34.7, 24.8, 21.2; IR (Neat Film NaCl) 2939, 1695,1596, 1504, 1462, 1405, 1279, 1252, 1181, 1122, 1107, 1045, 1025, 968,891, 752 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₁H₂₄NO₂ [M+H]⁺:322.1802, found 322.1803.

(E)-1-(2-Methoxyphenyl)-3-(3-(4-methoxyphenyl)allyl)pyrrolidin-2-one(SI16)

Lactam SI16 was prepared according to the general procedure 2 using(E)-1-(3-chloroprop-1-en-1-yl)-4-methoxybenzene¹⁷ in place of methyliodide, and isolated by flash column chromatography (1:3 EtOAc:hexanes)on silica gel as a pale yellow oil. 100% yield. ¹H NMR (500 MHz, CDCl₃)δ 7.42-7.18 (m, 4H), 7.02-6.94 (m, 2H), 6.94-6.82 (m, 2H), 6.45 (dt,J=15.8, 1.4 Hz, 1H), 6.14 (dt, J=15.7, 7.1 Hz, 1H), 3.81 (s, 3H), 3.81(s, 3H), 3.76-3.60 (m, 2H), 2.81-2.69 (m, 2H), 2.54-2.43 (m, 1H),2.37-2.26 (m, 1H), 2.02-1.91 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1,158.9, 154.8, 131.5, 130.3, 128.6, 128.6, 127.4, 127.2, 125.2, 120.9,113.9, 112.0, 55.6, 55.3, 48.2, 42.0, 34.7, 24.8; IR (Neat Film NaCl)2934, 1694, 1606, 1510,1505, 1463, 1406, 1249, 1175, 1027, 753 cm⁻¹;HRMS (MM: ESI-APCI+) m/z calc'd for C₂₁H₂₄NO₃ [M+H]⁺: 338.1751, found338.1748.

(E)-3-(3-(4-Fluorophenyl)allyl)-1-(2-methoxyphenyl)pyrrolidin-2-one(SI17)

Lactam SI17 was prepared according to the general procedure 2 using(E)-1-(3-chloroprop-1-en-1-yl)-4-fluorobenzene¹⁸ in place of methyliodide, and isolated by flash column chromatography (1:3 EtOAc:hexanes)on silica gel as a white solid. 52% yield. ¹H NMR (500 MHz, CDCl₃) δ7.37-7.30 (m, 2H), 7.30-7.21 (m, 2H), 7.05-6.93 (m, 4H), 6.51-6.43 (m,1H), 6.20 (dt, J=15.8, 7.1 Hz, 1H), 3.81 (s, 3H), 3.75-3.61 (m, 2H),2.83-2.73 (m, 2H), 2.56-2.45 (m, 1H), 2.38-2.27 (m, 1H), 1.96 (ddt,J=12.8, 8.6, 7.6 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 163.0,161.1, 154.8, 133.7, 133.6, 131.0, 128.7, 128.6, 127.6, 127.5, 127.3,127.8, 127.2, 120.9, 115.5, 115.3, 112.0, 55.6, 48.2, 41.9, 34.7, 24.9;IR (Neat Film NaCl) 2942, 1696, 1597, 1507, 1458, 1405, 1279, 1253,1225, 1158, 1046, 1025, 968, 839, 753 cm⁻¹; HRMS (MM: ESI-APCI+) m/zcalc'd for C₂₀H₂₁FNO₂ [M+H]⁺: 326.1551, found 326.1544.

(E)-1-(2-Methoxyphenyl)-3-(3-(thiophen-3-yl)ally)pyrrolidin-2-one (SI18)

Lactam SI18 was prepared according to the general procedure 2 using(E)-3-(3-chloroprop-1-en-1-yl)thiophene in place of methyl iodide, andisolated by flash column chromatography (1:2 EtOAc:hexanes) on silicagel as a pale yellow oil. 62% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.19(m, 4H), 7.10 (dd, J=3.1, 1.2 Hz, 1H), 7.01-6.92 (m, 2H), 6.52 (d,J=15.7 Hz, 1H), 6.13 (dt, J=15.7, 7.1 Hz, 1H), 3.81 (s, 3H), 3.75-3.59(m, 2H), 2.81-2.71 (m, 2H), 2.53-2.42 (m, 1H), 2.37-2.26 (m, 1H),2.02-1.90 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.1, 154.8, 140.1,128.6, 128.6, 127.3, 127.3, 126.4, 125.9, 125.0, 121.0, 120.9, 112.1,55.6, 48.2, 41.9, 34.6, 24.9; IR (Neat Film NaCl) 2936, 1694, 1596,1504, 1463, 1408, 1279, 1252, 1181, 1122, 1046, 1025, 966, 890, 862, 753cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₈H₂₀NO₂S [M+H]⁺: 314.1209,found 314.1206.

1-(2-Methoxyphenyl)-3-((2E,4E)-5-phenylpenta-2,4-dien-1-yl)pyrrolidin-2-one(SI19)

Lactam SI19 was prepared according to the general procedure 2 using((1E,3E)-5-bromopenta-1,3-dien-1-y)benzene²° in place of methyl iodide,and isolated by flash column chromatography (1:2 EtOAc:hexanes) onsilica gel as a colorless oil. 73% yield. ¹H NMR (500 MHz, CDCl₃) δ7.42-7.36 (m, 2H), 7.36-7.17 (m, 4H), 7.02-6.92 (m, 2H), 6.79 (ddd,J=15.7, 10.4, 0.8 Hz, 1H), 6.49 (d, J=15.7 Hz, 1H), 6.33 (ddd, J=15.1,10.4, 0.8 Hz, 1H), 5.93-5.83 (m, 1H), 3.83 (s, 3H), 3.76-3.61 (m, 2H),2.80-2.68 (m, 2H), 2.47-2.37 (m, 1H), 2.36 -2.26 (m, 1H), 1.99-1.87 (m,1H); ¹³C NMR (126 MHz, CDCl₃) δ 176.0, 154.8, 137.4, 132.8, 132.0,130.9, 129.0, 128.6, 128.6, 128.6, 127.4, 127.3, 126.2, 120.9, 112.0,55.6, 48.1, 41.9, 34.6, 25.0; IR (Neat Film NaCl) 2941, 1694, 1596,1505, 1463, 1407, 1300, 1279, 1252, 1181, 1123, 1107, 1046, 1026, 992,911, 891, 750, 693 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₂H₂₄NO₂[M+H]⁺: 334.1802, found 334.1801.

General Procedure for Ni-Catalyzed C-Acylation

General procedure 3:(S)-1-(2-methoxyphenyl)-3-methyl-3-(4-methylbenzoyl) pyrrolidin-2-one(6)

To a suspension of lactam 1b (82.1 mg, 0.400 mmol, 2.00 equiv),p-tolunitrile 2a (23.4 mg, 0.200 mmol, 1.00 equiv), bromobenzene 3b(31.5 μL, 0.300 mmol, 1.50 equiv), LHMDS (40.2 mg, 0.240 mmol, 1.20equiv) and LiBr (86.9 mg, 1.00 mmol, 5.00 equiv) in toluene (1.0 mL) andTHF (0.20 mL) was added a solution of Ni(COD)₂ (5.50 mg, 0.0200 mmol,0.100 equiv) and SL-M004-1 (Solvias, 25.3 mg, 0.0240 mmol, 0.120 equiv)at 0° C. and the reaction mixture was stirred at 0° C. for 48 h. AcOEt(6 mL) and 1 M HCl aqueous solution (5 mL) were added and the mixturewas stirred at ambient temperature for 1 h. The reaction mixture wasextracted with AcOEt (24 mL), washed with brine (5 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by flash column chromatography (1:5 EtOAc:hexanes) on silicagel to give lactam 6 as a white solid (59.4 mg, 92% yield, 91% ee).[α]_(D) ²⁵ +2.1° (c 1.03, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.09-8.02(m, 2H), 7.33-7.20 (m, 4H), 7.03-6.95 (m, 2H), 3.94-3.87 (m, 1H), 3.85(s, 3H), 3.84-3.78 (m, 1H), 2.94 (ddd, J=12.9, 8.4, 6.4 Hz, 1H), 2.40(s, 3H), 2.07 (ddd, J=12.8, 8.0, 4.8 Hz, 1H), 1.68 (s, 3H); ¹³C NMR (126MHz, CDCl₃) δ 198.4, 174.9, 155.0, 143.2, 133.0, 129.6, 129.0, 129.0,128.4, 126.9, 120.9, 112.1, 56.6, 55.7, 47.1, 32.5, 21.6; IR (Neat FilmNaCl) 2973, 2929, 1701, 1696, 1606, 1503, 1459, 1408, 1272, 1255, 1185,1121, 1023, 1009, 970, 753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₀H₂₂NO₃ [M+H]⁺: 324.1594, found 324.1599.

Ni-Catalyzed C-Acylation Products(S)-3-Benzoyl-1-(4-methoxyphenyl)-3-methylpyrrolidin-2-one (4a)

Lactam 4a was prepared according to the general procedure 3 from 1ausing benzonitrile in place of p-tolunitrile, reacting at ambienttemperature for 24 h in place of 0° C. for 48 h, and isolated by flashcolumn chromatography (1:10 EtOAc:hexanes) on silica gel as a whitesolid. 86% yield, 88% ee. [α]_(D) ²⁵ −27.1° (c 1.45, CHCl₃); ¹H NMR (500MHz, CDCl₃) δ 8.07-8.00 (m, 2H), 7.58-7.47 (m, 3H), 7.46-7.38 (m, 2H),6.96-6.87 (m, 2H), 3.95 (ddd, J=9.5, 7.9, 6.1 Hz, 1H), 3.86 (ddd, J=9.6,8.2, 5.1 Hz, 1H), 3.82 (s, 3H), 2.93 (ddd, J=13.0, 8.0, 5.1 Hz, 1H),2.08 (ddd, J=12.9, 8.3, 6.1 Hz, 1H), 1.68 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 2930, 199.0, 173.2, 156.9, 135.9, 132.5, 132.4, 129.2, 128.4,121.8, 114.1, 58.3, 55.5, 46.5, 31.7, 22.0; IR (Neat Film NaCl) 1685,1512, 1399, 1268, 1249, 1182, 1090, 1032, 970, 830, 702 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₁₉H₂₀NO₃ [M+H]⁺: 310.1438, found 310.1442.

(S)-3-Benzoyl-1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one (4b)

Lactam 4b was prepared according to the general procedure 3 from 1busing benzonitrile in place of p-tolunitrile, and isolated by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel as a whitesolid. 81% yield, 92% ee. [α]_(D) ²⁵ +4.0° (c1.21, CHCl₃, 92% ee); ¹HNMR (500 MHz, CDCl₃) δ 8.17-8.11 (m, 2H), 7.56-7.48 (m, 1H), 7.47-7.40(m, 2H), 7.34-7.25 (m, 2H), 7.04-6.95 (m, 2H), 3.90 (ddd, J=9.6, 8.4,4.8 Hz, 1H), 3.86-3.78 (m, 1H), 3.85 (s, 3H), 2.95 (ddd, J=12.9, 8.4,6.3 Hz, 1H), 2.08 (ddd, J=12.8, 8.0, 4.8 Hz, 1H), 1.69 (s, 3H); ¹³C NMR(126 MHz, CDCl₃) δ 1989.0, 174.7, 155.0, 135.8, 132.4, 129.4, 129.0,128.3, 128.3, 126.8, 121.0, 112.1, 56.8, 55.7, 47.1, 32.4, 21.6; IR(Neat Film NaCl) 2974, 2930, 1701, 1697, 1596, 1503, 1459, 1410, 1305,1270, 1256, 1121, 1023, 1010, 970, 750, 702 cm⁻¹; HRMS (MM: ESI-APCI+)m/z calc'd for C₁₉H_(b 20)NO₃ [M+]³⁰ : 310.1438, found 310.1441.

(S)-3-Benzoyl-l-(3,5-dimethoxyphenyl)-3-methylpyrrolidin-2-one (4c)

Lactam 4c was prepared according to the general procedure 3 from 1cusing benzonitrile in place of p-tolunitrile, and isolated by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel as a whitesolid. 80% yield, 85% ee. [α]_(D) ²⁵ −30.0° (c 1.04, CHCl₃); ¹H NMR (500MHz, CDCl₃) δ 8.04-7.97 (m, 2H), 7.55-7.48 (m, 1H), 7.47-7.38 (m, 2H),6.92 (d, J=2.2 Hz, 2H), 6.31 (t, J=2.2 Hz, 1H), 3.97 (ddd, J=9.6, 8.0,6.0 Hz, 1H), 3.87 (ddd, J=9.6, 8.3, 5.1 Hz, 1H), 3.81 (s, 6H), 2.92(ddd, J=13.1, 8.0, 5.2 Hz, 1H), 2.07 (ddd, J=12.9, 8.3, 6.0 Hz, 1H),1.68 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 198.6, 173.8, 160.9, 141.0,135.7, 132.6, 129.2, 128.4, 98.3, 97.1, 58.7, 55.5, 46.4, 31.4, 22.0; IR(Neat Film NaCl) 2937, 2840, 1696, 1598, 1480, 1393, 1277, 1249, 1206,1156, 1067, 972, 834, 722, 699, 682, 661 cm⁻¹; HRMS (MM: ESI-APCI+) m/zcalc'd for C₂₀H₂₂NO₄ [M+H]⁺: 340.1543, found 340.1552.

(S)-3-Benzoyl-1-(2-isopropoxyphenyl)-3-methylpyrrolidin-2-one (4d)

Lactam 4d was prepared according to the general procedure 3 from 1dusing benzonitrile in place of p-tolunitrile, and isolated by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel as a whitesolid. 69% yield, 86% ee. [α]_(D) ²⁵ +9.4° (c 1.01, CHCl₃); ¹HNMR (500MHz, CDCl₃) δ 8.21-8.14 (m, 2H), 7.59-7.51 (m, 1H), 7.51-7.43 (m, 2H),7.35-7.26 (m, 2H), 7.06-6.97 (m, 2H), 4.63 (hept, J=6.1 Hz, 1H), 3.98(ddd, J=9.5, 8.2, 4.9 Hz, 1H), 3.85 (ddd, J=9.6, 8.0, 6.3 Hz, 1H), 3.00(ddd, J=12.8, 8.2, 6.3 Hz, 1H), 2.10 (ddd, J=12.8, 8.0, 4.9 Hz, 1H),1.73 (s, 3H), 1.36 (d, J=6.0 Hz, 3H), 1.35 (d, J=6.0 Hz, 3H); ¹³C NMR(126 MHz, CDCl₃) δ 199.0, 174.5, 153.2, 135.9, 132.4, 129.4, 128.8,128.8, 128.3, 127.7, 120.6, 114.1, 70.4, 56.9, 47.2, 32.6, 22.1, 22.1,21.6; IR (Neat Film NaCl) 2977, 2930, 1697, 1596, 1500, 1455, 1407,1281, 1270, 1255, 1124, 954, 750, 701cm⁻¹; HRMS (MM: ESI-APCI+) m/zcalc'd for C₂₁H₂₄NO₃ [M+H]⁺: 338.1751, found 338.1744.

(S)-1-(2-Methoxyphenyl)-3-methyl-3-(3-methylbenzoyl)pyrrolidin-2-one (7)

Lactam 7 was prepared according to the general procedure 3 from 1b usingm-tolunitrile in place of p-tolunitrile, and isolated by flash columnchromatography (1:5 EtOAc:hexanes) on silica gel as a colorless oil. 91%yield, 93% ee. [α]_(D) ²⁵ +5.5° (c 0.52, CHCl₃); ¹H NMR (500 MHz, CDCl₃)δ 7.97-7.90 (m, 1H), 7.89-7.88 (m, 1H), 7.33-7.26 (m, 4H), 7.04-6.95 (m,2H), 3.90 (ddd, J=9.6, 8.4, 4.7 Hz, 1H), 3.86-3.78 (m, 1H), 3.84 (s,3H), 2.93 (ddd, J=12.9, 8.4, 6.5 Hz, 1H), 2.40 (s, 3H), 2.11-2.02 (m,1H), 1.67 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 199.3, 174.8, 155.06,138.0, 135.8, 133.1, 129.8, 129.0, 128.3, 128.1, 126.9, 126.5, 121.0,112.1, 56.8, 55.7, 47.1, 32.4, 21.6, 21.5; IR (Neat Film NaCl) 2973,2931, 1694, 1598, 1504, 1455, 1409, 1276, 1255, 1182, 1121, 1092, 1044,1024, 976, 905, 789, 754, cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₀H₂₂NO₃ [M+H]⁺: 324.1594, found 324.1602.

(S)-l-(2-Methoxyphenyl)-3-methyl-3-(2-methylbenzoyl)pyrrolidin-2-one (8)

Lactam 8 was prepared according to the general procedure 3 from 1b usingo-tolunitrile in place of p-tolunitrile, reacting with aqueous HCl at70° C. in place of ambient temperature, and isolated by flash columnchromatography (1:5 EtOAc:hexanes) on silica gel as a colorless oil. 69%yield, 94% ee. [α]_(D) ²⁵ 29.6° (c 0.20, CHCl₃); ^(1H) NMR (500 MHz,CDCl₃) δ 7.64 (dd, J=7.6, 1.4 Hz, 1H), 7.34-7.25 (m, 2H), 7.25-7.16 (m,3H), 7.01-6.93 (m, 2H), 3.82 (s, 3H), 3.73 (dd, J=7.6, 6.3 Hz, 2H),2.82-2.73 (m, 1H), 2.33 (s, 3H), 2.14-2.05 (m, 1H), 1.59 (s, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 205.5, 173.8, 154.9, 139.1, 135.6, 130.9, 129.7,128.9, 128.4, 126.9, 126.0, 125.2, 120.9, 112.1, 58.4, 55.6, 47.2, 31.9,21.3, 20.1; IR (Neat Film NaCl) 2971, 2932, 1694, 1597, 1505, 1456,1409, 1305, 1281, 1256, 1122, 1045, 1025, 969, 755 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₂₀H₂₂NO₃ [M+H]⁺: 324.1594, found 324.1601.

(S)-3-(4-(tert-Butyl)benzoyl)-1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one(9)

Lactam 9 was prepared according to the general procedure 3 from 1b using4-(tert-butyl)benzonitrile in place of p-tolunitrile, and isolated byflash column chromatography (1:5 EtOAc:hexanes) on silica gel as a whitesolid. 89% yield, 92% ee. [α]_(D) ²⁵ +6.9° (c 1.04, CHCl₃); ¹H NMR (500MHz, CDCl₃) ∂ 8.13-8.07 (m, 2H), 7.47-7.41 (m, 2H), 7.33-7.25 (m, 2H),7.04-6.95 (m, 2H), 3.93-3.80 (m, 2H), 3.85 (s, 3H), 2.96 (ddd, J=12.9,8.4, 6.5 Hz, 1H), 2.08 (ddd, J=12.8, 7.9, 4.8 Hz, 1H), 1.69 (s, 3H),1.34 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 198.2, 175.0, 156.0, 155.0,132.7, 129.5, 128.9, 128.4, 126.9, 125.2, 120.9, 112.1, 56.6, 55.7,47.1, 35.0, 32.5, 31.1, 21.6; IR (Neat Film NaCl) 2963, 1701, 1676,1603, 1504, 1459, 1406, 1272, 1255, 1121, 1109, 1023, 971, 752 cm⁻¹;HRMS (MM: ESI-APCI+) m/z calc'd for C₂₃H₂₈NO₃ [M+H]⁺: 366.2064, found366.2072.

(S)-3-(4-Methoxybenzoyl)-1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one(10)

Lactam 10 was prepared according to the general procedure 3 from 1busing 4-methoxybenzonitrile in place of p-tolunitrile, and isolated byflash column chromatography (1:5 EtOAc:hexanes) on silica gel as acolorless oil. 85% yield, 89% ee. [α]_(D) ²⁵ −3.7° (c 0.73, CHCl₃); ¹HNMR (500 MHz, CDCl₃) δ 8.24-8.17 (m, 2H), 7.32-7.27 (m, 2H), 7.03-6.88(m, 4H), 3.93-3.87 (m, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.83-3.77 (m,1H), 2.97 (ddd, J=12.8, 8.2, 6.2 Hz, 1H), 2.07 (ddd, J=12.9, 8.0, 5.0Hz, 1H), 1.68 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 196.8, 175.0, 162.9,155.0, 132.1, 128.9, 128.3, 128.2, 127.0, 120.9, 113.4, 112.1, 56.6,55.7, 55.4, 47.2, 32.7, 21.8; IR (Neat Film NaCl) 2971, 2933, 1695,1600, 1504, 1464, 1456, 1410, 1307, 1259, 1174, 1027, 971, 845, 754,699, 610 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₀H₂₂NO₄ [M+H]⁺:340.1543, found 340.1547.

(S)-3-(4-Fluorobenzoyl)-1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one(11)

Lactam 11 was prepared according to the general procedure 3 from 1busing 4-fluorobenzonitrile in place of p-tolunitrile, and isolated byflash column chromatography (1:5 EtOAc:hexanes) on silica gel as a whitesolid. 36% yield, 96% ee. [α]_(D) ²⁵ −1.8° (c 0.77, CHCl₃); ¹H NMR (500MHz, CDCl₃) δ 8.28-8.20 (m, 2H), 7.34-7.27 (m, 1H), 7.27-7.20 (m, 1H),7.14-7.06 (m, 2H), 7.04-6.95 (m, 2H), 3.91 (ddd, J=9.6, 8.3, 5.0 Hz,1H), 3.85-3.76 (m, 4H), 3.83 (s, 3H), 2.95 (ddd, J=12.8, 8.3, 6.1 Hz,1H), 2.12-2.03 (m, 1H), 1.68 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 197.1,174.5, 165.2, 154.9, 132.4, 131.9, 129.1, 128.3, 126.7, 121.0, 115.3,112.1, 56.9, 55.7, 47.2, 32.5, 21.7; IR (Neat Film NaCl) 2974, 1697,1684, 1597, 1506, 1457, 1410, 1271, 1256, 1235, 1160, 1024, 972, 848,754, 609 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₉H₁₉FNO₃ [M+H]⁺:328.1343, found 328.1353.

(S)-1-(2-Methoxyphenyl)-3-methyl-3-(4-(trifluoromethyl)benzoyl)pyrrolidin-2-one(12)

Lactam 12 was prepared according to the general procedure 3 from 1busing 4-trifluoromethylbenzonitrile in place of p-tolunitrile, andisolated by flash column chromatography (1:5 EtOAc:hexanes) on silicagel as a colorless oil. 23% yield, 87% ee. [α]_(D) ²⁵ +2.7° (c 0.71,CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.29-8.22 (m, 2H), 7.78-7.61 (m, 2H),7.35-7.29 (m, 1H), 7.24 (dd, J=7.7, 1.7 Hz, 1H), 7.05-6.95 (m, 2H), 3.91(ddd, J=9.7, 8.3, 5.0 Hz, 1H), 3.84 (s, 3H), 3.83-3.77 (m, 1H), 2.93(ddd, J=12.9, 8.3, 6.2 Hz, 1H), 2.09 (ddd, J=13.0, 8.0, 5.0 Hz, 1H),1.69 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 198.4, 174.1, 154.9, 139.0,133.7, 133.6, 129.7, 129.2, 128.3, 125.3, 123.6, 121.0, 112.1, 57.2,55.7, 47.2, 32.1, 21.5; IR (Neat Film NaCl) 2975, 2934, 1697, 1505,1409, 1328, 1316, 1257, 1169, 1127, 1068, 1020, 1009, 973, 858, 753;cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₀H₁₉F₃NO₃ [M+H]⁺: 378.1312,found 378.1325.

(S)-3-(2-Naphthoyl)-1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one (13)

Lactam 13 was prepared according to the general procedure 3 from 1busing 2-naphthonitrile in place of p-tolunitrile, and isolated by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel as a colorlessoil. 66% yield, 91% ee. [α]_(D) ²⁵ +15.8° (c 0.52, CHCl₃); ¹HNMR (500MHz, CDCl₃) δ 8.77 (d, J=1.3 Hz, 1H), 8.14 (dd, J=8.6, 1.8 Hz, 1H),7.98-7.92 (m, 1H), 7.87 (t, J=8.4 Hz, 2H), 7.62-7.56 (m, 1H), 7.56-7.49(m, 1H), 7.35-7.27 (m, 2H), 7.06-6.97 (m, 2H), 3.96 (ddd, J=9.6, 8.3,4.9 Hz, 1H), 3.90-3.81 (m, 1H), 3.84 (s, 3H), 3.04 (ddd, J=12.9, 8.3,6.2 Hz, 1H), 2.17-2.08 (m, 1H), 1.75 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ198.9, 174.7, 155.0, 135.1, 133.0, 132.4, 131.1, 129.8, 129.0, 128.3,128.3, 128.0, 127.6, 127.0, 126.5, 125.4, 121.0, 112.2, 57.1, 55.7,47.2, 32.6, 21.8; IR (Neat Film NaCl) 2930, 1694, 1505, 1463, 1409,1281, 1255, 1120, 1024, 750 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₃H₂₂NO₃ [M+H]⁺: 360.1594, found 360.1589.

(S)-3-Ethyl-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one (14)

Lactam 14 was prepared according to the general procedure 3 from SI6,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a colorless oil. 50% yield, 77% ee. [α]_(D) ²⁵ +14.6° (c0.81, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=8.3 Hz, 2H),7.31-7.18 (m, 4H), 7.01-6.92 (m, 2H), 3.90 (ddd, J=9.5, 8.1, 6.7 Hz,1H), 3.79 (s, 3H), 3.71 (ddd, J=9.5, 8.7, 4.3 Hz, 1H), 2.95 (ddd,J=13.0, 8.0, 4.2 Hz, 1H), 2.41-2.30 (m, 4H), 2.17-2.05 (m, 2H), 0.97 (t,J=7.5 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 198.3, 173.5, 154.9, 143.0,134.0, 129.5, 128.9, 128.9, 128.4, 127.1, 120.9, 112.1, 61.8, 55.6,47.5, 29.5, 29.1, 21.6, 8.8; IR (Neat Film NaCl) 2962, 1700, 1606, 1504,1461, 1253, 1159, 1024, 752 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₁H₂₄NO₃ [M+H]⁺: 338.1751, found 338.1753.

(S)-3-Benzyl-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one(15)

Lactam 15 was prepared according to the general procedure 3 from SI7,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a colorless oil. 61% yield, 81% ee. [α]_(D) ²⁵ +62.3° (c0.90, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.13-8.06 (m, 2H), 7.31-7.16 (m,8H), 6.93-6.83 (m, 3H), 3.77 (s, 3H), 3.62 (td, J=9.1, 4.1 Hz, 1H), 3.53(d, J=13.7 Hz, 1H), 3.34 (d, J=13.7 Hz, 1H), 2.90-2.72 (m, 2H), 2.37 (s,3H), 2.26 (ddd, J=13.0, 8.4, 4.1 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ197.7, 173.1, 154.9, 143.2, 136.7, 133.3, 130.6, 129.7, 129.0, 128.9,128.4, 127.9, 126.9, 126.7, 120.8, 112.0, 61.4, 55.6, 47.0, 40.9, 28.7,21.7; IR (Neat Film NaCl) 2928, 1696, 1604, 1502, 1457, 1405, 1240,1185, 1025, 741, 702 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₆H₂₆NO₃[M+H]⁺: 400.1907, found 400.1919.

(S)-3-(4-Methoxybenzyl)-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one(16)

Lactam 16 was prepared according to the general procedure 3 from SI8,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a colorless oil. 77% yield, 81% ee. [α]_(D) ²⁵ +50.4° (c1.21, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.16-8.09 (m, 2H), 7.30-7.18 (m,5H), 6.99 (dd, J=8.0, 1.8 Hz, 1H), 6.98-6.88 (m, 2H), 6.88-6.80 (m, 2H),3.81 (s, 3H), 3.80 (s, 3H), 3.67 (td, J=9.2, 4.2 Hz, 1H), 3.51 (d,J=13.9 Hz, 1H), 3.32 (d, J=13.9 Hz, 1H), 2.95 (ddd, J=9.4, 8.6, 6.5 Hz,1H), 2.80 (ddd, J=13.3, 9.0, 6.4 Hz, 1H), 2.40 (s, 3H), 2.27 (ddd,J=13.0, 8.6, 4.2 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 197.9, 173.2,158.7, 154.9, 143.1, 133.4, 131.5, 129.7, 129.0, 128.8, 128.6, 127.9,126.7, 120.8, 113.7, 112.0, 61.5, 55.6, 55.3, 47.0, 40.1, 28.7, 21.6; IR(Neat Film NaCl) 2930, 1694, 1606, 1505, 1463, 1409, 1301, 1248, 1180,1028, 832, 753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₇H₂₈NO₄[M+H]⁺: 430.2013, found 430.2006.

(S)-3-(4-Fluorobenzyl)-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one(17)

Lactam 17 was prepared according to the general procedure 3 from SI9,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a white foam. 76% yield, 74% ee. [α]_(D) ²⁵ +38.9° (c3.08, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.15-8.08 (m, 2H), 7.31-7.21 (m,5H), 7.04-6.91 (m, 5H), 3.79 (s, 3H), 3.67 (td, J=9.3, 4.4 Hz, 1H), 3.54(d, J=13.9 Hz, 1H), 3.34 (d, J=13.9 Hz, 1H), 3.00 (ddd, J=9.5, 8.7, 6.3Hz, 1H), 2.81 (ddd, J=13.4, 9.1, 6.3 Hz, 1H), 2.41 (s, 3H), 2.26 (ddd,J=13.3, 8.7, 4.4 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 197.6, 172.9,163.1, 161.1, 154.8, 143.3, 133.2, 132.4, 132.0, 132.0, 129.6, 129.1,128.9, 127.8, 126.5, 120.9, 115.3, 115.1, 112.0, 61.4, 55.6, 47.0, 40.1,28.6, 21.7; IR (Neat Film NaCl) 2931, 1697, 1604, 1504, 1465, 1410,1222, 1185, 1026, 909, 833, 752, 731 cm⁻¹; HRMS (MM: ESI-APCI+) m/zcalc'd for C₂₆H₂₅FNO₃ [M+H]⁺: 418.1813, found 418.1806.

(R)-1-(2-Methoxyphenyl)-3-(4-methylbenzoyl)-3-(2,2,2-trifluoroethyl)pyrrolidin-2-one(18)

Lactam 18 was prepared according to the general procedure 3 from SI10,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a colorless oil. 58% yield, 71% ee. [α]_(D) ²⁵ +10.3° (c2.16, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.16-8.09 (m, 2H), 7.34-7.28 (m,1H), 7.28-7.17 (m, 3H), 7.03-6.92 (m, 2H), 4.00 (ddd, J=9.6, 7.7, 6.8Hz, 1H), 3.78 (s, 3H), 3.72 (ddd, J=9.6, 8.7, 3.9 Hz, 1H), 3.34 (dq,J=15.8, 11.1 Hz, 1H), 3.10-3.01 (m, 1H), 2.87 (dq, J=15.7, 11.1 Hz, 1H),2.40 (s, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 195.1, 171.4, 154.8, 143.5,133.0, 129.6, 129.3, 129.1, 128.1, 127.5, 126.4, 125.3, 121.0, 112.0,57.7, 55.6, 47.6, 39.3, 39.1, 38.9, 38.7, 29.1, 29.0, 21.6; IR (NeatFilm NaCl) 2952, 1703, 1673, 1505, 1464, 1373, 1299, 1260, 1143, 1021,753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₁H₂₁F₃NO₃ [M+H]⁺:392.1468, found 392.1459.

(S)-3-(3-(Benzyloxy)propyl)-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one(19)

Lactam 19 was prepared according to the general procedure 3 from SI11,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a colorless oil. 67% yield, 60% ee. [α]_(D) ²⁵ +9.3° (c2.90, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.16-8.10 (m, 1H), 7.37-7.18 (m,6H), 7.01-6.92 (m, 1H), 4.45 (d, J=2.3 Hz, 1H), 3.88 (ddd, J=9.5, 8.0,6.6 Hz, 1H), 3.77 (s, 1H), 3.76-3.66 (m, 1H), 3.46 (td, J=6.4, 1.1 Hz,1H), 2.38 (s, 2H), 2.19-2.07 (m, 1H), 1.77-1.58 (m, 1H); ¹³C NMR (126MHz, CDCl₃) δ 198.0, 173.4, 154.9, 143.0, 138.5, 133.8, 129.5, 128.9,128.9, 128.4, 128.3, 127.6, 127.5, 127.0, 120.9, 112.0, 72.8, 70.3,61.1, 55.6, 47.5, 32.8, 30.0, 24.8, 21.6; IR (Neat Film NaCl) 2935,1698, 1606, 1504, 1455, 1408, 1302, 1279, 1252, 1185, 1101, 1027, 750,699 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₉H₃₂NO₄ [M+H]⁺:458.2326, found 458.2315.

(S)-1-(2-Methoxyphenyl)-3-(4-methylbenzoyl)-3-(3-methylbut-2-en-1-yl)pyrrolidin-2-one(20)

Lactam 20 was prepared according to the general procedure 3 from SI12,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a pale yellow oil. 71% yield, 76% ee. [α]_(D) ²⁵ +29.6° (c2.15, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.14-8.07 (m, 2H), 7.32-7.25 (m,2H), 7.25-7.18 (m, 2H), 7.02-6.92 (m, 2H), 5.23-5.15 (m, 1H), 3.88 (ddd,J=9.5, 8.5, 5.7 Hz, 1H), 3.83 (s, 3H), 3.68 (ddd, J=9.4, 8.7, 5.1 Hz,1H), 3.02-2.93 (m, 1H), 2.89-2.73 (m, 2H), 2.39 (s, 3H), 2.14 (ddd,J=13.0, 8.7, 5.7 Hz, 1H), 1.72 (s, 3H), 1.59 (s, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 198.2, 173.5, 155.0, 142.9, 135.5, 133.8, 129.5, 128.9, 128.9,128.3, 127.1, 120.9, 118.6, 112.1, 61.1, 55.6, 47.5, 34.5, 29.2, 26.1,21.6, 18.0; IR (Neat Film NaCl) 2917, 1698, 1606, 1504, 1463, 1408,1248, 1184, 1123, 1024, 753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₄H₂₈NO₃ [M+H]⁺: 378.2064, found 378.2060.

(S,E)-3-(But-2-en-1-yl)-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one(21)

Lactam 21 was prepared according to the general procedure 3 from SI13,and isolated by flash column chromatography (1:8 EtOAc:hexanes) onsilica gel as a pale yellow oil. 70% yield, 86% ee. [α]_(D) ²⁵ +45.5° (c2.10, CHCl₃); ^(1H) NMR (500 MHz, CDCl₃) δ 8.08 (d, J=8.3 Hz, 2H),7.34-7.19 (m, 4H), 7.03-6.94 (m, 2H), 5.63-5.43 (m, 2H), 3.92-3.86 (m,1H), 3.84 (s, 3H), 3.73-3.62 (m, 1H), 2.94-2.72 (m, 3H), 2.39 (s, 3H),2.20 (ddd, J=13.2, 8.7, 5.3 Hz, 1H), 1.68 (dq, J=6.3, 1.2 Hz, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 198.0, 173.5, 155.0, 143.0, 133.7, 129.8, 129.5,129.5, 128.9, 128.3, 127.0, 125.4, 120.9, 112.1, 60.7, 55.6, 47.4, 39.1,28.9, 21.6, 18.2; IR (Neat Film NaCl) 2917, 1698, 1606, 1504, 1463,1408, 1254, 1185, 1122, 1045, 1024, 973, 837, 750 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₂₃H₂₆NO₃ [M+H]⁺: 364.1907, found 364.1909.

(S)-3-Cinnamyl-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one(22)

Lactam 22 was prepared according to the general procedure 3 from SI14,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a white foam. 60% yield, 86% ee. [α]_(D) ²⁵ +55.5° (c0.93, CHCl₃); ^(1H) NMR (500 MHz, CDCl₃) δ 8.11-8.05 (m, 2H), 7.41-7.33(m, 2H), 7.33-7.18 (m, 10H), 7.00-6.93 (m, 2H), 6.52 (d, J=15.8 Hz, 1H),6.29 (dt, J=15.5, 7.6 Hz, 1H), 3.92-3.82 (m, 1H), 3.80 (s, 3H), 3.75(ddd, J=9.6, 8.7, 5.7 Hz, 1H), 3.05 (dt, J=7.4, 1.4 Hz, 2H), 2.85 (ddd,J=13.3, 8.9, 5.8 Hz, 1H), 2.41 (s, 2H), 2.30 (ddd, J=13.5, 8.7, 5.0 Hz,1H); ¹³C NMR (126 MHz, CDCl₃) δ 197.9, 173.3, 155.0, 143.1, 137.3,134.2, 133.5, 129.4, 129.0, 129.0, 128.5, 128.3, 127.4, 126.8, 126.2,124.8, 121.0, 112.1, 60.7, 55.6, 47.3, 39.4, 28.8, 21.6; IR (Neat FilmNaCl) 2961, 1698, 1606, 1504, 1463, 1409, 1279, 1255, 1185, 1025, 971,911, 742, 694 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₈H₂₈NO₃[M+H]⁺: 426.2064, found 426.2067.

(S,E)-1-(2-Methoxyphenyl)-3-(4-methylbenzoyl)-3-(3-(p-tolyl)allyl)pyrrolidin-2-one(23)

Lactam 23 was prepared according to the general procedure 3 from SI15,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a pale yellow oil. 85% yield, 88% ee. [α]_(D) ²⁵ +56.0° (c2.93, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d, J=8.3 Hz, 2H),7.33-7.25 (m, 2H), 7.25-7.19 (m, 4H), 7.14-7.08 (m, 2H), 7.00-6.93 (m,2H), 6.49 (d, J=15.7 Hz, 1H), 6.23 (dt, J=15.5, 7.6 Hz, 1H), 3.92-3.83(m, 1H), 3.81 (s, 3H), 3.78-3.69 (m, 1H), 3.04 (d, J=7.6 Hz, 2H), 2.85(ddd, J=13.2, 8.9, 5.8 Hz, 1H), 2.40 (s, 3H), 2.39-2.25 (m, 4H); ¹³C NMR(126 MHz, CDCl₃) δ 197.9, 173.4, 155.0, 143.1, 137.1, 134.5, 134.0,133.5, 129.4, 129.2, 129.0, 129.0, 128.3, 126.8, 126.1, 123.6, 121.0,112.0, 60.7, 55.6, 47.4, 39.4, 28.8, 21.6, 21.2; IR (Neat Film NaCl)2920, 1694, 1606, 1505, 1463, 1409, 1279, 1254, 1184, 1121, 1045, 1025,974, 911, 838, 752 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₉H₃₀NO₃[M+H]⁺: 440.2220, found 440.2220.

(S,E)-1-(2-Methoxyphenyl)-3-(3-(4-methoxyphenyl)allyl)-3-(4-methylbenzoyl)pyrrolidin-2-one (24)

Lactam 24 was prepared according to the general procedure 3 from SI16,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a white foam. 68% yield, 88% ee. [α]_(D) ²⁵ +57.6° (c1.09, CHCl₃, 88% ee); ¹H NMR (500 MHz, CDCl₃) δ 8.11-8.05 (m, 2H),7.34-7.26 (m, 3H), 7.26-7.17 (m, 3H), 7.00-6.93 (m, 2H), 6.87-6.81 (m,2H), 6.46 (d, J=15.7 Hz, 1H), 6.13 (dt, J=15.5, 7.5 Hz, 1H), 3.88 (td,J=9.2, 4.9 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.80-3.67 (m, 1H), 3.03(dt, J=7.6, 1.4 Hz, 2H), 2.85 (ddd, J=13.2, 8.9, 5.8 Hz, 1H), 2.40 (s,3H), 2.35-2.23 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 197.9, 173.4, 159.0,155.0, 143.1, 133.5, 130.1, 129.4, 129.0, 128.9, 128.3, 127.4, 126.8,122.4, 121.0, 113.9, 112.1, 60.8, 55.6, 55.3, 47.4, 39.4, 28.8, 21.6; IR(Neat Film NaCl) 2957, 1699, 1607, 1505, 1464, 1249, 1175, 1027, 838,752 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₉H₃NO₄ [M+H]⁺: 456.2169,found 456.2164.

(S,E)-3-(3-(4-Fluorophenyl)allyl)-1-(2-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolidin-2-one (25)

Lactam 25 was prepared according to the general procedure 3 from SI17,and isolated by flash column chromatography (1:10 EtOAc:hexanes) onsilica gel as a white foam. 62% yield, 83% ee. [α]_(D) ²⁵ +40.7° (c0.55, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.07 (d, J=8.3 Hz, 2H),7.35-7.26 (m, 3H), 7.26-7.22 (m, 2H), 7.22-7.18 (m, 1H), 7.06-6.93 (m,4H), 6.51-6.44 (m, 1H), 6.20 (dt, J=15.5, 7.6 Hz, 1H), 3.88 (ddd, J=9.6,8.9, 5.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.69 (m, 1H), 3.04 (ddd, J=7.2,3.6, 1.3 Hz, 2H), 2.86 (ddd, J=13.2, 8.9, 5.7 Hz, 1H), 2.41 (s, 3H),2.38-2.23 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 197.8, 173.2, 163.1,161.2, 154.9, 143.2, 133.5, 132.9, 129.4, 129.1, 129.0, 128.2, 127.7,126.8, 124.6, 121.0, 115.5, 115.3, 112.1, 60.7, 55.6, 47.3, 39.3, 28.9,21.6; IR (Neat Film NaCl) 2944, 1693, 1604, 1505, 1460, 1412, 1254,1228, 1184, 1158, 1045, 1024, 910, 838, 753, 731 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₂₈H₂₇FNO₃ [M+H]⁺: 444.1969, found 444.1969.

(S,E)-1-(2-Methoxyphenyl)-3-(4-methylbenzoyl)-3-(3-(thiophen-3-yl)allyl)pyrrolidin-2-one (26)

Lactam 26 was prepared according to the general procedure 3 from SI18,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a pale yellow oil. 76% yield, 83% ee. [α]_(D) ²⁵ +46.7° (c1.17, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.12-8.01 (m, 2H), 7.33-7.14 (m,6H), 7.10 (dd, J=3.0, 1.2 Hz, 1H), 7.00-6.93 (m, 2H), 6.53 (d, J=15.7Hz, 1H), 6.13 (dt, J=15.5, 7.6 Hz, 1H), 3.88 (td, J=9.1, 4.9 Hz, 1H),3.81 (s, 3H), 3.79-3.68 (m, 1H), 3.01 (dd, J=7.7, 1.3 Hz, 2H), 2.85(ddd, J=13.3, 8.9, 5.8 Hz, 1H), 2.40 (s, 3H), 2.28 (ddd, J=13.5, 8.8,5.0 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 197.8, 173.3, 155.0, 143.2,139.9, 133.4, 129.4, 129.0, 129.0, 128.4, 128.2, 126.8, 126.0, 125.0,124.6, 121.5, 121.0, 112.1, 60.7, 55.6, 47.3, 39.3, 28.8, 21.6; IR (NeatFilm NaCl) 2958, 1698, 1606, 1504, 1463, 1409, 1302,1279, 1254, 1184,1122, 1024, 967, 836, 753 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₆H₂₅NO₃S [M+H]⁺: 432.1628, found 432.1622.

(S)-1-(2-Methoxyphenyl)-3-(4-methylbenzoyl)-3-((2E,4E)-5-phenylpenta-2,4-dien-1-yl)pyrrolidin-2-one(27)

Lactam 27 was prepared according to the general procedure 3 from SI19,and isolated by flash column chromatography (1:5 EtOAc:hexanes) onsilica gel as a pale yellow oil. 35% yield, 84% ee. [α]_(D) ²⁵ +40.6° (c1.45, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=8.3 Hz, 2H),7.42-7.36 (m, 2H), 7.36-7.16 (m, 6H), 6.98 (d, J=7.8 Hz, 2H), 6.76 (ddd,J=15.7, 10.5, 0.9 Hz, 1H), 6.49 (d, J=15.7 Hz, 1H), 6.38-6.29 (m, 1H),5.87 (dt, J=15.2, 7.7 Hz, 1H), 3.90 (ddd, J=9.5, 8.8, 5.1 Hz, 1H), 3.85(s, 3H), 3.77-3.69 (m, 1H), 3.08-2.92 (m, 2H), 2.86 (ddd, J=13.2, 8.8,5.6 Hz, 1H), 2.41 (s, 3H), 2.25 (ddd, J=13.7, 8.8, 5.2 Hz, 1H); ¹³C NMR(126 MHz, CDCl₃) δ 197.8, 173.2, 155.0, 143.1, 137.3, 134.8, 133.5,131.6, 129.5, 129.1, 129.0, 129.0, 128.7, 128.6, 128.4, 127.4, 126.8,126.3, 121.0, 112.1, 60.8, 55.7, 47.3, 39.3, 29.0, 21.6; IR (Neat FilmNaCl) 3024, 1694, 1606, 1505, 1463, 1409, 1304, 1253, 1185, 1122, 1045,1026, 992, 910, 747, 693 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₃₀H₃₀NO₃ [M+H]⁺: 452.2220, found 452.2220.

Derivatization of C-Acylation Products

(S)-3-Benzoyl-3-methylpyrrolidin-2-one (28)

To a solution lactam 4e (93% ee, 40.0 mg, 0.129 mmol, 1.00 equiv) inMeCN (0.6 mL) and water (0.6 mL) was added CAN (424 mg, 0.774 mmol, 6.00equiv) and the reaction mixture was stirred at 70° C. for 24 h. Thereaction mixture was allowed to cool to ambient temperature and brine (5mL) was added. The reaction mixture was extracted with AcOEt (30 mL),dried over Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by flash column chromatography (1:2 to 2:1 EtOAc:hexanes)on silica gel to give lactam 28 as a white solid (19.6 mg, 75% yield).[α]_(D) ²⁵ +25.7° (c 0.20, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.05-7.99(m, 2H), 7.56-7.48 (m, 1H), 7.47-7.39 (m, 2H), 5.83 (s, 1H), 3.59-3.50(m, 1H), 3.50-3.42 (m, 1H), 2.92 (ddd, J=13.4, 8.1, 5.5 Hz, 1H), 2.08(ddd, J=13.3, 8.1, 5.5 Hz, 1H), 1.60 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ199.1, 178.3, 135.7, 132.5, 129.1, 128.4, 55.9, 39.6, 34.5, 21.5; IR(Neat Film NaCl) 3246, 2978, 1667, 1595, 1444, 1307, 1265, 1207, 1008,973, 782, 701, 651 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₁₂H₁₄NO₂[M+H]⁺: 204.1019, found 204.1015.

(S)-3-((S)-Hydroxy(phenyl)methyl)-1-(2-methoxyphenyl)-3-methylpyrrolidin-2-one(29)

To a solution lactam 4e (92% ee, 99.5 mg, 0.322 mmol, 1.00 equiv) in TFA(1.6 mL) was added Et₃SiH (0.102 mL, 643 mmol, 2.00 equiv) and thereaction mixture was stirred at ambient temperature for 24 h. CH₂Cl₂ (4mL) and 2 M NaOH aqueous solution (8 mL) was added and the reactionmixture was stirred at ambient temperature for 3 h. The mixture wasextracted with CH₂Cl₂ (30 mL, twice), washed with brine (10 mL), driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by flash column chromatography (1:2 EtOAc:hexanes) on silicagel to give lactam 29 as a white solid (90.2 mg, 90% yield). [α]_(D) ²⁵−12.5° (c 1.10, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.49-7.43 (m, 2H),7.43-7.27 (m, 4H), 7.22 (dd, J=7.7, 1.7 Hz, 1H), 7.03-6.94 (m, 2H), 5.18(br s, 1H), 4.99 (s, 1H), 3.84 (s, 3H), 3.69 (td, J=9.4, 6.9 Hz, 1H),3.54 (ddd, J=9.6, 8.8, 2.2 Hz, 1H), 2.31 (dt, J=12.6, 9.0 Hz, 1H), 1.54(ddd, J=12.6, 6.9, 2.2 Hz, 1H), 1.27 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ180.3, 154.8, 139.4, 129.1, 128.5, 127.9, 127.7, 127.3, 126.5, 120.9,112.1, 77.8, 55.7, 47.3, 46.9, 30.8, 15.6; IR (Neat Film NaCl) 3400,2966, 1672, 1596, 1504, 1459, 1413, 1305, 1281, 1256, 1180, 1161, 1121,1082, 1046, 1026, 917, 885, 753, 725, 703, cm⁻¹; HRMS (MM: ESI-APCI+)m/z calc'd for C₁₉H₂₂NO₃ [M+H]⁺: 312.1594, found 312.1595.

(R)-1-(4-Methoxyphenyl)-3-methyl-2-oxopyrrolidin-3-yl benzoate (30)

To a solution lactam 4a (88% ee, 30.9 mg, 0.100 mmol, 1.00 equiv) inCH₂Cl₂ (1 mL) and were added NaHCO₃ (42.0 mg, 0.500 mmol, 5.00 equiv)and m-CPBA (75%, 115.0 mg, 0.500 mmol, 5.00 equiv) and the reactionmixture was stirred at ambient temperature for 20 h. 10% NaHCO₃ aqueoussolution (3 mL) and brine (3 mL) were added and the mixture wasextracted with CH₂C₁₂ (30 mL, twice), dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel to give lactam30 as a white solid (17.1 mg, 53% yield, 88% ee). [α]²⁵ −3.3° (c 0.25,CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 8.10-8.00 (m, 2H), 7.63-7.51 (m, 3H),7.47-7.40 (m, 2H), 6.96-6.89 (m, 2H), 3.96 (td, J=9.6, 3.2 Hz, 1H), 3.82(s, 3H), 2.84-2.74 (m, 1H), 2.40 (ddd, J=13.3, 8.1, 3.2 Hz, 1H), 1.75(d, J=0.7 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 171.2, 165.5, 156.9,133.2, 132.5, 129.9, 129.9, 128.3, 121.9, 114.1, 81.2, 55.5, 44.9, 30.6,23.3; IR (Neat Film NaCl) 2963, 1705, 1512, 1451, 1403, 1317, 1292,1251, 1136, 1116, 1091, 1072, 1032, 828, 715 cm⁻¹; HRMS (MM: ESI-APCI+)m/z calc'd for C₁₉H₂₀NO₄ [M+H]⁺: 326.1387, found 326.1381.

(R)-4-Methoxyphenyl-1-(2-methoxyphenyl)-3-methyl-2-oxopyrrolidine-3-carboxylate(31)

To a solution lactam 10 (160 mg, 0.471 mmol, 1.00 equiv) in CH₂Cl₂ (9.4mL) was added m-CPBA (75%, 1.08 g, 4.71 mmol, 10.0 equiv) and thereaction mixture was stirred at ambient temperature for 24 h and thenrefluxed for 48 h. The reaction mixture was allowed to cool to ambienttemperature and 10% Na₂SO₃ aqueous solution (30 mL) and saturated NaHCO₃aqueous solution (10 mL) were added. The mixture was extracted withCH₂Cl₂ (130 mL), washed with brine (20 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel to give lactam31 as a pale yellow oil (54.2 mg, 32% yield). [α]_(D) ²⁵ −11.7° (c 0.56,CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.32-7.27 (m, 2H), 7.09-7.02 (m, 2H),7.02-6.93 (m, 2H), 6.93-6.85 (m, 2H), 3.92-3.75 (m, 2H), 3.81 (s, 3H),3.80 (s, 3H), 2.84 (ddd, J=12.9, 7.8, 4.5 Hz, 1H), 2.21 (ddd, J=12.9,8.3, 6.8 Hz, 1H), 1.67 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.9, 171.6,157.3, 154.9, 144.3, 129.0, 128.6, 126.9, 122.2, 120.9, 114.4, 112.1,55.7, 55.6, 51.8, 47.1, 32.1, 20.2; IR (Neat Film NaCl) 2936, 1760,1699, 1597, 1505, 1463, 1410, 1305, 1251, 1193, 1112, 1088, 1027, 754cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd for C₂₀H₂₂NO₅ [M+H]⁺: 356.1492,found 356.1489.

(R)-Ethyl-1-(2-methoxyphenyl)-3-methyl-2-oxopyrrolidine-3-carboxylate(32)

To a solution lactam 31 (36.0 mg, 0.101 mmol, 1.00 equiv) in EtOH (2.0mL) was added K₂CO₃ (70.0 mg, 0.506 mmol, 5.00 equiv) and the reactionmixture was stirred at ambient temperature for 30 h. The reactionmixture was concentrated under reduced pressure and brine was added tothe residue. The mixture was extracted with AcOEt (15 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by flash column chromatography (1:2 EtOAc:hexanes) on silicagel to give lactam 32 as a pale yellow oil (20.5 mg, 73% yield). [α]_(D)²⁵ −14.6° (c 0.98, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.24 (m, 2H),7.03-6.88 (m, 2H), 4.31-4.17 (m, 2H), 3.83 (s, 3H), 3.82-3.70 (m, 2H),2.64 (ddd, J=12.8, 7.0, 4.7 Hz, 1H), 2.14-2.04 (m, 1H), 1.55 (s, 3H),1.31 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.3, 172.6, 154.9,128.8, 128.5, 127.1, 120.9, 112.1, 61.5, 55.7, 51.6, 47.1, 32.2, 20.3,14.2; IR (Neat Film NaCl) 2979, 1738, 1699, 1597, 1505, 1456, 1409,1257, 1195, 1137, 1090, 1024, 754 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'dfor C₁₅H₂₀NO₄ [M+H]⁺: 278.1387, found 278.1384.

(R)-E thyl-3-methyl-2-oxopyrrolidine-3-carboxylate (33)

To a solution lactam 32 (20.0 mg, 0.0721 mmol, 1.00 equiv) in MeCN (1.5mL) and water (1.5 mL) was added CAN (237 mg, 0.433 mmol, 6.00 equiv)and the reaction mixture was stirred at 40° C. for 24 h. The reactionmixture was allowed to cool to ambient temperature and 10% Na₂SO₃aqueous solution (3 mL) and brine (3 mL) were added. The reactionmixture was extracted with AcOEt (20 mL, twice), dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (2:1 EtOAc:hexanes) on silica gel to give lactam28 as a white solid (2.0 mg, 16% yield). [α]_(D) ²⁵ +19.5° (c 0.09,MeOH) (reported data [α]_(D) ²⁵ +19.0° (c 2, MeOH))⁸; ¹H NMR (500 MHz,CDCl₃) δ 5.83 (br s, 1H), 4.21 (m, 2H), 3.53-3.44 (m, 1H), 3.40-3.31 (m,1H), 2.65 (ddd, J=12.8, 7.8, 4.0 Hz, 1H), 2.05 (ddd, J=13.0, 8.4, 7.0Hz, 1H), 1.46 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃)δ 2981, 176.6, 172.2, 61.6, 50.5, 39.4, 34.0, 20.1, 14.1; IR (Neat FilmNaCl) 3245, 2981, 1703, 1454, 1266, 1196, 1138, 1028 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₈H₁₄NO₃ [M+H]⁺: 171.0968, found 171.0965.

Isolation and Reduction of Potential Imine Intermediates

(S)-1-(4-Methoxyphenyl)-3-methyl-3-((phenylimino)(o-tolypmethyl)pyrrolidin-2-one(34)

To a suspension of lactam 1a (82.1 mg, 0.400 mmol, 2.00 equiv),o-tolunitrile 2b (23.4 mg, 0.200 mmol, 1.00 equiv), bromobenzene 3b(31.5 μL, 0.300 mmol, 1.5 equiv), LHMDS (40.2 mg, 0.240 mmol, 1.20equiv) and LiBr (86.9 mg, 1.00 mmol, 5.00 equiv) in toluene (1.0 mL) andTHF (0.20 mL) were added a solution of Ni(COD)₂ (5.50 mg, 0.0200 mmol,0.100 equiv) and SL-M004-1(Solvias, 25.3 mg, 0.0240 mmol, 0.120 equiv)at 25° C. and the reaction mixture was stirred at 25° C. for 24 h. Thereaction mixture was filtered through a pad of silica gel eluting withAcOEt (60 mL). The eluate was concentrated under reduced pressure andthe residue was purified by flash column chromatography (1:10EtOAc:hexanes) on silica gel to give imine 34 as a white foam (62 mg,77% yield, 60/40 mixture of E/Z isomers). ¹H NMR (500 MHz, CDCl₃) formajor isomer: δ 7.65-6.62 (m, 8H), 3.86 (s, 3H), 3.76 (ddd, J=9.3, 8.2,4.6 Hz, 1H), 3.62 (ddd, J=9.3, 7.9, 6.6 Hz, 1H), 2.68 (ddd, J=12.6, 7.9,4.6 Hz, 1H), 2.17 (ddd, J=12.8, 8.2, 6.6 Hz, 1H), 2.06 (s, 3H), 1.66 (s,3H); for minor isomer: δ 7.61-6.62 (m, 8H), 4.09 (dt, J=9.1, 7.7 Hz,1H), 3.85 (s, 3H), 3.82 (td, J=8.8, 3.6 Hz, 1H), 3.15 (ddd, J=12.5, 7.8,3.6 Hz, 1H), 2.27-2.20 (m, 1H), 2.07 (s, 3H), 1.66 (s, 3H); ¹³C NMR (126MHz, CDCl₃) for major and minor isomer: δ 175.1, 174.8, 174.7, 172.2,156.7, 149.9, 136.1, 135.8, 134.2, 133.3, 132.9, 132.7, 130.1, 129.8,128.4, 128.3, 128.1, 128.0, 124.8, 124.7, 123.56, 123.4, 122.98, 122.0,120.59, 120.3, 114.0, 55.8, 55.5, 54.7, 47.0, 46.3, 33.4, 31.2, 22.5,22.0, 20.5, 20.3; IR (Neat Film NaCl) 2931, 1688, 1512, 1485, 1398,1289, 1249, 1181, 1090, 1033, 993, 829, 766, 731, 697 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₂₆H₂₇N₂O₂ [M+H]⁺: 399.2067, found 399.2072.

(S)-1-(2-Methoxyphenyl)-3-methyl-3-(phenyl(phenylamino)methyl)pyrrolidin-2-one(36)

To a suspension of lactam 1b (82.1 mg, 0.400 mmol, 2.00 equiv),benzonitrile 2a (20.6 mg, 0.200 mmol, 1.00 equiv), bromobenzene 3b (31.5μL, 0.300 mmol, 1.5 equiv), LHMDS (40.2 mg, 0.240 mmol, 1.20 equiv) andLiBr (86.9 mg, 1.00 mmol, 5.00 equiv) in toluene (1.0 mL) and THF (0.20mL) were added a solution of Ni(COD)₂ (5.50 mg, 0.0200 mmol, 0.100equiv) and SL-M004-1 (Solvias, 25.3 mg, 0.0240 mmol, 0.120 equiv) at 0°C. and the reaction mixture was stirred at 0° C. for 48 h. NaBH₄ (45.4mg, 1.20 mmol, 6 equiv), THF (2 mL) and MeOH (2 mL) were added and thereaction mixture was stirred at 25° C. for 2 days. Water was added andthe mixture was extracted with AcOEt (50 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (1:5 EtOAc:hexanes) on silica gel to give amine 36as a colorless oil (54.3 mg, 70% yield).

Spectroscopic data for amine 36 was taken after separation of thediastereomers by flash column chromatography on silica gel.

Major isomer: ¹H NMR (500 MHz, CDCl₃) δ 7.54-7.48 (m, 2H), 7.38-7.31 (m,2H), 7.31-7.23 (m, 5H), 7.12 (dd, J=7.7, 1.7 Hz, 1H), 7.06-6.99 (m, 2H),6.99-6.88 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.50 (d, J=7.9 Hz, 2H), 5.51(s, 1H), 4.50 (s, 1H), 3.63-3.51 (m, 2H), 3.60 (s, 3H), 2.42 (ddd,J=12.7, 7.6, 4.7 Hz, 1H), 1.81 (ddd, J=13.0, 8.3, 6.8 Hz, 1H), 1.34 (s,3H); ¹³C NMR (126 MHz, CDCl₃) δ 177.9, 154.9, 148.3, 139.8, 129.0,128.9, 128.6, 128.6, 128.2, 127.5, 127.0, 120.8, 117.4, 114.1, 112.9,62.9, 55.4, 47.6, 46.7, 31.0, 19.7; IR (Neat Film NaCl) 3375, 2968,1678, 1601, 1505, 1455, 1310, 1279, 1260, 1025, 749, 702 cm⁻¹; HRMS (MM:ESI-APCI+) m/z calc'd for C₂₅H₂₇N₂O₂ [M+H]⁺: 387.2067, found 387.2070.

Minor isomer: ¹H NMR (500 MHz, CDCl₃) δ 7.48-7.42 (m, 2H), 7.35-7.20 (m,4H), 7.09-6.98 (m, 3H), 6.98-6.90 (m, 2H), 6.58-6.47 (m, 3H), 6.19 (brs, 1H), 4.37 (s, 1H), 3.78 (s, 3H), 3.41 (td, J=9.1, 4.7 Hz, 1H), 2.62(ddd, J=9.4, 8.4, 6.4 Hz, 1H), 2.27 (ddd, J=13.1, 8.4, 4.7 Hz, 1H), 1.98(ddd, J=13.0, 8.9, 6.4 Hz, 1H), 1.61 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ177.3, 154.6, 147.2, 140.6, 129.0, 128.8, 128.3, 128.3, 127.7, 127.5,126.8, 120.7, 116.4, 112.9, 112.0, 64.5, 55.6, 47.2, 46.75, 30.8, 24.8;IR (Neat Film NaCl) 3375, 2929, 1674, 1600, 1505, 1455, 1418, 1308,1256, 1026, 748, 704 cm⁻¹; HRMS (MM: ESI-APCI+) m/z calc'd forC₂₅H₂₇N₂O₂ [M+H]⁺: 387.2067, found 387.2071.

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Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

Equivalents

While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the disclosure will become apparent to those skilledin the art upon review of this specification and the claims below. Thefull scope of the disclosure should be determined by reference to theclaims, along with their full scope of equivalents, and thespecification, along with such variations.

1. A method for the preparation of a compound of formula (I):

comprising treating a compound of formula (II):

or a salt thereof; with a Ni(0) catalyst comprising a chiral ligand; anaryl nitrile; and an aryl halide; wherein, as valence and stabilitypermit, R¹ represents hydrogen or optionally substituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl,—C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl),—C(O)0(heteroaryl), —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or —NR¹⁰R¹¹; or R¹ or a sub stituent onring A taken together with a sub stituent on ring A and the interveningatoms, form an optionally substituted aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group; R²represents substituted or unsubstituted alkyl, alkenyl, alkynyl,aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl, heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,heterocycloalkyl, alkoxy, amino, or halo; R¹⁰ and R¹¹ are independentlyselected for each occurrence from hydrogen or substituted orunsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,heterocycloalkyl, alkenyl, and alkynyl; and ring A represents anoptionally substituted heterocycloalkyl, or heterocycloalkenyl group. 2.The method of claim 1, wherein the compound of formula (I) isrepresented by formula (Ia):

and the compound of formula (II) is represented by formula (IIa):

wherein: R⁴ represents hydrogen or optionally substituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl,—C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl),—C(O)O(heteroaryl), —C(O)O(heteroaralkyl), —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or —NR¹⁰R¹¹; R⁵ and R⁶ eachindependently represent hydrogen, hydroxyl, halogen, nitro, alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino,alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl,ether, thioether, ester, amido, thioester, carbonate, carbamate, urea,sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;B, D, and E independently for each occurrence represent, as valencepermits, O, S, NR⁴, CR⁵R⁶, C(O), CR⁵, or N; provided that no twoadjacent occurrences of N, B, D, and E are NR⁴, O, S, or N; or any twooccurrences of R¹, R⁴, R⁵, and R⁶ on adjacent N, B, D, or E groups,taken together with the intervening atoms, form an optionallysubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group; each occurrence of

independently represents a double bond or a single bond as permitted byvalence; and m and n are integers each independently selected from 0, 1,and
 2. 3. The method of claim 2, wherein the sum of m and n is 0, 1, 2,or
 3. 4. The method of claim 2, wherein each occurrence of B, D, and Eis independently —CR⁵R⁶—, or —CR⁵—, or —C(O)—.
 5. The method of claim 2,wherein E is —CR⁵—; and the sum of m and n is
 0. 6. The method of claim5, wherein R¹ is selected from optionally substituted alkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, alkenyl, —C(O)alkyl, —C(O)aryl,—C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl),—C(O)O(heteroaralkyl), and —S(O)₂(aryl); R⁵ is selected from hydrogen,hydroxyl, halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl,alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, andacylamino; or R^(l) and the occurrence of R⁵ on E are taken together toform an optionally substituted heteroaryl, heterocycloalkyl, orheterocycloalkenyl group. 7-10. (canceled)
 11. The method of claim 1,wherein the compound of formula (I) is represented by formula (Ib):

and the compound of formula (II) is represented by formula (IIb):


12. The method of claim 11, wherein R¹ is selected from optionallysubstituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl,—C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl,—C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl),—C(O)O(heteroaryl), —C(O)O(heteroaralkyl), and —S(O)₂(aryl); R⁵ isselected from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, alkylamino, amido, and acylamino; or R¹ and R⁵ on E aretaken together to form an optionally substituted heteroaryl,heterocycloalkyl, or heterocycloalkenyl group. 13-15. (canceled)
 16. Themethod of claim 1, wherein R² represents substituted or unsubstitutedalkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl,heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, or halo.
 17. (canceled) 18.(canceled)
 19. The method of claim 1, wherein the Ni(0) catalyst isNi[(1,5-cyclooctadiene)₂].
 20. The method of claim 1, wherein the Ni(0)catalyst is used in an amount from about 0.1 mol % to about 20 mol %relative to the compound of formula (II).
 21. (canceled)
 22. (canceled)23. The method of claim 1, wherein the chiral ligand is anenantioenriched phosphine ligand. 24-27. (canceled)
 28. The method ofclaim 1, wherein the chiral ligand is used in an amount from about 0.5mol % to about 50 mol % relative to the compound of formula (II). 29.(canceled)
 30. The method of claim 1, wherein the aryl nitrile is anoptionally substituted benzonitrile or a napthonitrile. 31-33.(canceled)
 34. The method of claim 1, wherein the reaction is underacylation conditions.
 35. The method of claim 34, wherein the acylationconditions further comprise a base.
 36. (canceled)
 37. (canceled) 38.The method of claim 34, wherein the acylation conditions furthercomprise a lithium salt.
 39. (canceled)
 40. The method of claim 34,wherein acylation conditions include reaction in toluene,tetrahydrofuran, dioxane, methyl tent-butyl ether, dimethoxyethane, or amixture of toluene and tetrahydrofuran.
 41. (canceled)
 42. (canceled)43. The method of claim 34, wherein the acylation conditions furthercomprise adding an acidic solution.
 44. (canceled)
 45. The method ofclaim 1, whereby the compound of formula (I) is enantioenriched.